| 1 | Behav Pharmacol 2000 Jun 11: 235-42 |
|---|---|
| PMID | 11103878 |
| Title | Studies in animal models and humans suggesting a role of nerve growth factor in schizophrenia-like disorders. |
| Abstract | Neurotrophic factors, such as nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF), are known to play a crucial role in growth, differentiation and function in a variety of brain neurons during development and in adult life. We have recently shown that environmental changes, aggressive behavior and anxiety-like responses alter both circulating and brain basal NGF levels. In the present review, we present data obtained using animal models which suggest that neurotrophic factors, particularly NGF and BDNF, might be implicated in mechanism(s) leading to a condition associated with schizophrenic-like behaviors. The hypothesis that neurotrophins of the NGF family can be implicated in some maldevelopmental aspects of schizophrenia is supported by findings indicating that the constitutive levels of NGF and BDNF are affected in schizophrenic patients. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypal |
| 2 | Behav Pharmacol 2000 Jun 11: 235-42 |
| PMID | 11103878 |
| Title | Studies in animal models and humans suggesting a role of nerve growth factor in schizophrenia-like disorders. |
| Abstract | Neurotrophic factors, such as nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF), are known to play a crucial role in growth, differentiation and function in a variety of brain neurons during development and in adult life. We have recently shown that environmental changes, aggressive behavior and anxiety-like responses alter both circulating and brain basal NGF levels. In the present review, we present data obtained using animal models which suggest that neurotrophic factors, particularly NGF and BDNF, might be implicated in mechanism(s) leading to a condition associated with schizophrenic-like behaviors. The hypothesis that neurotrophins of the NGF family can be implicated in some maldevelopmental aspects of schizophrenia is supported by findings indicating that the constitutive levels of NGF and BDNF are affected in schizophrenic patients. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypal |
| 3 | J. Neurosci. Res. 2000 Jun 60: 783-94 |
| PMID | 10861791 |
| Title | Brain-derived neurotrophic factor and tyrosine kinase receptor TrkB in rat brain are significantly altered after haloperidol and risperidone administration. |
| Abstract | The antipsychotics haloperidol and risperidone are widely used in the therapy of schizophrenia. The former drug mainly acts on the dopamine (DA) D(2) receptor whereas risperidone binds to both DA and serotonin (5HT) receptors, particularly in the neurons of striatal and limbic structures. Recent evidence suggests that neurotrophins might also be involved in antipsychotic action in the central nervous system (CNS). We have previously reported that haloperidol and risperidone significantly affect brain nerve growth factor (NGF) level suggesting that these drugs influence the turnover of endogenous growth factors. Brain-derived neurotrophic factor (BDNF) supports survival and differentiation of developing and mature brain DA neurons. We hypothesized that treatments with haloperidol or risperidone will affect synthesis/release of brain BDNF and tested this hypothesis by measuring BDNF and TrkB in rat brain regions after a 29-day-treatment with haloperidol or risperidone added to chow. Drug treatments had no effects on weight of brain regions. Chronic administration of these drugs, however, altered BDNF synthesis or release and expression of TrkB-immunoreactivity within the brain. Both haloperidol and risperidone significantly decreased BDNF concentrations in frontal cortex, occipital cortex and hippocampus and decreased or increased TrkB receptors in selected brain structures. Because BDNF can act on a variety of CNS neurons, it is reasonable to hypothesize that alteration of brain level of this neurotrophin could constitute one of the mechanisms of action of antipsychotic drugs. These observations also support the possibility that neurotrophic factors play a role in altered brain function in schizophrenic disorders. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypal |
| 4 | J. Neurosci. Res. 2000 Jun 60: 783-94 |
| PMID | 10861791 |
| Title | Brain-derived neurotrophic factor and tyrosine kinase receptor TrkB in rat brain are significantly altered after haloperidol and risperidone administration. |
| Abstract | The antipsychotics haloperidol and risperidone are widely used in the therapy of schizophrenia. The former drug mainly acts on the dopamine (DA) D(2) receptor whereas risperidone binds to both DA and serotonin (5HT) receptors, particularly in the neurons of striatal and limbic structures. Recent evidence suggests that neurotrophins might also be involved in antipsychotic action in the central nervous system (CNS). We have previously reported that haloperidol and risperidone significantly affect brain nerve growth factor (NGF) level suggesting that these drugs influence the turnover of endogenous growth factors. Brain-derived neurotrophic factor (BDNF) supports survival and differentiation of developing and mature brain DA neurons. We hypothesized that treatments with haloperidol or risperidone will affect synthesis/release of brain BDNF and tested this hypothesis by measuring BDNF and TrkB in rat brain regions after a 29-day-treatment with haloperidol or risperidone added to chow. Drug treatments had no effects on weight of brain regions. Chronic administration of these drugs, however, altered BDNF synthesis or release and expression of TrkB-immunoreactivity within the brain. Both haloperidol and risperidone significantly decreased BDNF concentrations in frontal cortex, occipital cortex and hippocampus and decreased or increased TrkB receptors in selected brain structures. Because BDNF can act on a variety of CNS neurons, it is reasonable to hypothesize that alteration of brain level of this neurotrophin could constitute one of the mechanisms of action of antipsychotic drugs. These observations also support the possibility that neurotrophic factors play a role in altered brain function in schizophrenic disorders. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypal |
| 5 | Mol. Psychiatry 2002 -1 7: 1101-6 |
| PMID | 12476325 |
| Title | Identification of a novel variant of the human NR2B gene promoter region and its possible association with schizophrenia. |
| Abstract | N-methyl-D-aspartate (NMDA) receptor dysfunction is involved in the pathogenesis of schizophrenia. We determined the nucleotide sequence of the 5'-upstream region of the human NMDA receptor 2B (NR2B) subunit gene and identified a novel T-200G variant located in one of the Sp1 binding sites. To investigate the effect of this variant on the transcriptional activity of the hNR2B gene, we performed gene reporter assays using PC12 pheochromocytoma cells transiently transfected with luciferase reporter plasmids. In the absence of nerve growth factor (NGF), luciferase activities did not significantly differ between the two alleles and the control plasmid. However, luciferase reporter activity of the T allele was significantly up-regulated compared to that of the G allele in the presence of NGF (P = 0.0013), indicating that this polymorphic site is a critical region for NR2B gene regulation through NGF-induced Sp1-binding. A case control study showed that the frequency of the G allele (P = 0.0164) was significantly higher in 100 schizophrenics than in 100 controls. These findings suggest that the T-200G variant causes dysfunction of NMDA receptors consisting of the NR2B subunit and may be involved in the development of schizophrenia. Replication studies of independent samples and family-based association studies are necessary to further evaluate the significance of our findings. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypal |
| 6 | Mol. Psychiatry 2002 -1 7: 1101-6 |
| PMID | 12476325 |
| Title | Identification of a novel variant of the human NR2B gene promoter region and its possible association with schizophrenia. |
| Abstract | N-methyl-D-aspartate (NMDA) receptor dysfunction is involved in the pathogenesis of schizophrenia. We determined the nucleotide sequence of the 5'-upstream region of the human NMDA receptor 2B (NR2B) subunit gene and identified a novel T-200G variant located in one of the Sp1 binding sites. To investigate the effect of this variant on the transcriptional activity of the hNR2B gene, we performed gene reporter assays using PC12 pheochromocytoma cells transiently transfected with luciferase reporter plasmids. In the absence of nerve growth factor (NGF), luciferase activities did not significantly differ between the two alleles and the control plasmid. However, luciferase reporter activity of the T allele was significantly up-regulated compared to that of the G allele in the presence of NGF (P = 0.0013), indicating that this polymorphic site is a critical region for NR2B gene regulation through NGF-induced Sp1-binding. A case control study showed that the frequency of the G allele (P = 0.0164) was significantly higher in 100 schizophrenics than in 100 controls. These findings suggest that the T-200G variant causes dysfunction of NMDA receptors consisting of the NR2B subunit and may be involved in the development of schizophrenia. Replication studies of independent samples and family-based association studies are necessary to further evaluate the significance of our findings. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypal |
| 7 | J. Neurosci. Res. 2003 Nov 74: 605-13 |
| PMID | 14598305 |
| Title | Opposing effects of low and high-dose clozapine on survival of transgenic amyotrophic lateral sclerosis mice. |
| Abstract | Clozapine is a potent atypical neuroleptic or antipsychotic agent used to relieve symptoms of early-diagnosed schizophrenia. Aside from well-described dopamine and serotonin receptor blockade effects, clozapine may also be neuroprotective through its modulation of the p75 neurotrophin receptor (p75(NTR)) and superoxide dismutase 1 (SOD1) expression. The death-signalling activities of both p75(NTR) and mutant SOD1 are implicated in motor neuron degeneration in humans and transgenic mice with amyotrophic lateral sclerosis (ALS). We therefore investigated the effects of clozapine in cell culture and mouse models of ALS. Clozapine dose-dependently inhibited full-length and cleaved p75(NTR) but not SOD1 protein expression in the motor neuron-like (NSC-34) cell line. Furthermore, low concentrations of clozapine protected NSC-34 cells from paraquat-mediated superoxide toxicity, nerve growth factor (NGF)-induced death signalling, and serum deprivation, whereas high concentrations potentiated death. Systemic thrice-weekly administration of low and high-dose clozapine to mutant superoxide dismutase 1 (SOD1(G93A)) mice produced differential effects on disease onset and survival. Low-dose treatment was associated with delayed locomotor impairment and death, compared to high-dose clozapine, which accelerated paralysis and mortality (P < 0.05). Increased death was not attributable to toxicity, as clozapine-induced agranulocytosis was not detected from blood analysis. High-dose clozapine, however, produced extrapyramidal symptoms in mice manifest by hindlimb rigidity, despite reducing spinal cord p75(NTR) levels overall. These results suggest that although clozapine may exert p75(NTR)-mediated neuroprotective activity in vitro, its profound antagonistic effects on dopaminergic and serotonergic systems in vivo at high doses may exacerbate the phenotype of transgenic ALS mice. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypal |
| 8 | Zh Nevrol Psikhiatr Im S S Korsakova 2003 -1 103: 69-72 |
| PMID | 14564782 |
| Title | [A comparison of some indices of innate and adaptive immunity in different types of schizophrenia]. |
| Abstract | Leukocyte elastase (LE) blood serum activity as an index of innate immunity and autoimmune reactions to brain antigens i.e. a level of autoantiboies to nerve growth factor (NGF) as an index of adaptive immunity were studied in patients with attack-like and slow progressive schizophrenia. Compared to controls, higher LE activity accompanied by a significant increase of autoantibodies to NGF titers was found in patients with attack-like schizophrenia. In slow progressive schizophrenia, only higher LE activity was detected. Correlations between immunological parameters and some clinical appearances (positive and negative disorders) and disease course peculiarities were revealed. The results suggest an involvement of different parts of immune system in pathophysiology of attack-like and slow progressive schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypal |
| 9 | Schizophr. Res. 2003 Apr 60: 117-23 |
| PMID | 12591576 |
| Title | Nerve growth factor in never-medicated first-episode psychotic and medicated chronic schizophrenic patients: possible implications for treatment outcome. |
| Abstract | Nerve growth factor (NGF) has been found to play a crucial role in the neuroplasticity of predominantly cholinergic neurons in brain development, and neuronal survival following brain injury, which reflect in cognitive performance. Wide ranges of neurodevelopmental abnormalities have been reported in schizophrenic patients, who also show poor cognitive performance. We report plasma NGF levels in never-medicated first-episode psychotic (FEP; N=24) and chronic medicated schizophrenic patients (N=24). NGF levels were determined in plasma by Enzyme-Linked ImmunoSorbent Assay (ELISA). Plasma NGF levels were significantly lower in both FEP and medicated chronic patients as compared to normal subjects (P<0.001). However, NGF levels were significantly higher in chronic schizophrenic patients, which were treated with antipsychotics as compared to FEP (P<0.05). Moreover, NGF levels in chronic patients treated with atypical antipsychotics were markedly higher as compared to patients treated with typical antipsychotics (P<0.05). Lower NGF levels in FEP patients at the onset of psychosis may have implications for the neurodevelopmental abnormalities. However, higher NGF levels in chronic patients treated with atypical antipsychotics may have implications for the treatment outcome. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypal |
| 10 | J. Psychopharmacol. (Oxford) 2003 Dec 17: 439-45 |
| PMID | 14870957 |
| Title | Chronic cannabis abuse raises nerve growth factor serum concentrations in drug-naive schizophrenic patients. |
| Abstract | Long-term cannabis abuse may increase the risk of schizophrenia. Nerve growth factor (NGF) is a pleiotropic neurotrophic protein that is implicated in development, protection and regeneration of NFG-sensitive neurones. We tested the hypothesis that damage to neuronal cells in schizophrenia is precipitated by the consumption of cannabis and other neurotoxic substances, resulting in raised NGF serum concentrations and a younger age for disease onset. The NGF serum levels of 109 consecutive drug-naive schizophrenic patients were measured and compared with those of healthy controls. The results were correlated with the long-term intake of cannabis and other illegal drugs. Mean (+/- SD) NGF serum levels of 61 control persons (33.1 +/- 31.0 pg/ml) and 76 schizophrenics who did not consume illegal drugs (26.3 +/- 19.5 pg/ml) did not differ significantly. schizophrenic patients with regular cannabis intake (> 0.5 g on average per day for at least 2 years) had significantly raised NGF serum levels of 412.9 +/- 288.4 pg/ml (n = 21) compared to controls and schizophrenic patients not consuming cannabis (p < 0.001). In schizophrenic patients who abused not only cannabis, but also additional substances, NGF concentrations were as high as 2336.2 +/- 1711.4 pg/ml (n = 12). On average, heavy cannabis consumers suffered their first episode of schizophrenia 3.5 years (n = 21) earlier than schizophrenic patients who abstained from cannabis. These results indicate that cannabis is a possible risk factor for the development of schizophrenia. This might be reflected in the raised NGF-serum concentrations when both schizophrenia and long-term cannabis abuse prevail. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypal |
| 11 | J. Psychopharmacol. (Oxford) 2003 Dec 17: 439-45 |
| PMID | 14870957 |
| Title | Chronic cannabis abuse raises nerve growth factor serum concentrations in drug-naive schizophrenic patients. |
| Abstract | Long-term cannabis abuse may increase the risk of schizophrenia. Nerve growth factor (NGF) is a pleiotropic neurotrophic protein that is implicated in development, protection and regeneration of NFG-sensitive neurones. We tested the hypothesis that damage to neuronal cells in schizophrenia is precipitated by the consumption of cannabis and other neurotoxic substances, resulting in raised NGF serum concentrations and a younger age for disease onset. The NGF serum levels of 109 consecutive drug-naive schizophrenic patients were measured and compared with those of healthy controls. The results were correlated with the long-term intake of cannabis and other illegal drugs. Mean (+/- SD) NGF serum levels of 61 control persons (33.1 +/- 31.0 pg/ml) and 76 schizophrenics who did not consume illegal drugs (26.3 +/- 19.5 pg/ml) did not differ significantly. schizophrenic patients with regular cannabis intake (> 0.5 g on average per day for at least 2 years) had significantly raised NGF serum levels of 412.9 +/- 288.4 pg/ml (n = 21) compared to controls and schizophrenic patients not consuming cannabis (p < 0.001). In schizophrenic patients who abused not only cannabis, but also additional substances, NGF concentrations were as high as 2336.2 +/- 1711.4 pg/ml (n = 12). On average, heavy cannabis consumers suffered their first episode of schizophrenia 3.5 years (n = 21) earlier than schizophrenic patients who abstained from cannabis. These results indicate that cannabis is a possible risk factor for the development of schizophrenia. This might be reflected in the raised NGF-serum concentrations when both schizophrenia and long-term cannabis abuse prevail. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypal |
| 12 | J. Psychopharmacol. (Oxford) 2003 Dec 17: 439-45 |
| PMID | 14870957 |
| Title | Chronic cannabis abuse raises nerve growth factor serum concentrations in drug-naive schizophrenic patients. |
| Abstract | Long-term cannabis abuse may increase the risk of schizophrenia. Nerve growth factor (NGF) is a pleiotropic neurotrophic protein that is implicated in development, protection and regeneration of NFG-sensitive neurones. We tested the hypothesis that damage to neuronal cells in schizophrenia is precipitated by the consumption of cannabis and other neurotoxic substances, resulting in raised NGF serum concentrations and a younger age for disease onset. The NGF serum levels of 109 consecutive drug-naive schizophrenic patients were measured and compared with those of healthy controls. The results were correlated with the long-term intake of cannabis and other illegal drugs. Mean (+/- SD) NGF serum levels of 61 control persons (33.1 +/- 31.0 pg/ml) and 76 schizophrenics who did not consume illegal drugs (26.3 +/- 19.5 pg/ml) did not differ significantly. schizophrenic patients with regular cannabis intake (> 0.5 g on average per day for at least 2 years) had significantly raised NGF serum levels of 412.9 +/- 288.4 pg/ml (n = 21) compared to controls and schizophrenic patients not consuming cannabis (p < 0.001). In schizophrenic patients who abused not only cannabis, but also additional substances, NGF concentrations were as high as 2336.2 +/- 1711.4 pg/ml (n = 12). On average, heavy cannabis consumers suffered their first episode of schizophrenia 3.5 years (n = 21) earlier than schizophrenic patients who abstained from cannabis. These results indicate that cannabis is a possible risk factor for the development of schizophrenia. This might be reflected in the raised NGF-serum concentrations when both schizophrenia and long-term cannabis abuse prevail. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypal |
| 13 | Neurosci. Lett. 2004 Nov 371: 79-83 |
| PMID | 15500971 |
| Title | Brain-derived neurotrophic factor serum concentrations are increased in drug-naive schizophrenic patients with chronic cannabis abuse and multiple substance abuse. |
| Abstract | Neurotrophins such as nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) are critically implicated in development and maintenance of function of neurons. Neurodevelopment is reported to be impaired in schizophrenia and vulnerable schizophrenic brains may be more sensitive to toxic influences. Thus, cannabis as a neurotoxin, may be more harmful to schizophrenic brains than to non-schizophrenic brains when used chronically. And neurotoxic events may promote disease-onset and lead to exaggerated release of neurotrophins. We investigated 157 drug-naive first-episode schizophrenic patients and found significantly elevated BDNF serum concentrations (by up to 34%) in patients with chronic cannabis abuse (n = 35, p < 0.001) or multiple substance abuse (n = 20, p < 0.001) prior to disease onset. Drug-naive schizophrenic patients without cannabis consumption showed similar results to normal controls and cannabis controls without schizophrenia. Thus, raised BDNF serum levels are not related to schizophrenia and/or substance abuse itself but may reflect a cannabis-related idiosyncratic damage of the schizophrenic brain. In line with this hypothesis, disease onset was 5.2 years earlier in the cannabis-consuming group (p = 0.0111). |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypal |
| 14 | Neurosci. Lett. 2004 Nov 371: 79-83 |
| PMID | 15500971 |
| Title | Brain-derived neurotrophic factor serum concentrations are increased in drug-naive schizophrenic patients with chronic cannabis abuse and multiple substance abuse. |
| Abstract | Neurotrophins such as nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) are critically implicated in development and maintenance of function of neurons. Neurodevelopment is reported to be impaired in schizophrenia and vulnerable schizophrenic brains may be more sensitive to toxic influences. Thus, cannabis as a neurotoxin, may be more harmful to schizophrenic brains than to non-schizophrenic brains when used chronically. And neurotoxic events may promote disease-onset and lead to exaggerated release of neurotrophins. We investigated 157 drug-naive first-episode schizophrenic patients and found significantly elevated BDNF serum concentrations (by up to 34%) in patients with chronic cannabis abuse (n = 35, p < 0.001) or multiple substance abuse (n = 20, p < 0.001) prior to disease onset. Drug-naive schizophrenic patients without cannabis consumption showed similar results to normal controls and cannabis controls without schizophrenia. Thus, raised BDNF serum levels are not related to schizophrenia and/or substance abuse itself but may reflect a cannabis-related idiosyncratic damage of the schizophrenic brain. In line with this hypothesis, disease onset was 5.2 years earlier in the cannabis-consuming group (p = 0.0111). |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypal |
| 15 | Prog. Brain Res. 2004 -1 146: 151-65 |
| PMID | 14699963 |
| Title | Neurotrophic factors and CNS disorders: findings in rodent models of depression and schizophrenia. |
| Abstract | Nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) are proteins involved in neuronal survival and plasticity of dopaminergic, cholinergic and serotonergic neurons in the central nervous system (CNS). Loss of neurons in specific brain regions has been found in depression and schizophrenia, and this chapter summarizes the findings of altered neurotrophins in animal models of those two disorders under baseline condition and following antidepressive and antipsychotic treatments. In a model of depression (Flinders sensitive line/Flinders resistant line; FSL/FRL rats), increased NGF and BDNF concentrations were found in frontal cortex of female, and in occipital cortex of male 'depressed' FSL compared to FRL control rats. Using the same model, the effects of electroconvulsive stimuli (ECS) and chronic lithium treatment on brain NGF, BDNF and glial cell line-derived neurotrophic factors were investigated. ECS and lithium altered the brain concentrations of neurotrophic factors in the hippocampus, frontal cortex, occipital cortex and striatum. ECS mimic the effects of electroconvulsive therapy (ECT) that is an effective treatment for depression and also schizophrenia. Since NGF and BDNF may also be changed in the CNS of animal models of schizophrenia, we investigated whether treatment with antipsychotic drugs (haloperidol, risperidone, and olanzapine) affects the constitutive levels of NGF and BDNF in the CNS. Both typical and atypical antipsychotic drugs altered the regional brain levels of NGF and BDNF. Other studies also demonstrated that these drugs differentially altered neurotrophin mRNAs. Overall, these studies indicate that alteration of brain level of NGF and BDNF could constitute part of the biochemical alterations induced by antipsychotic drugs. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypal |
| 16 | World J. Biol. Psychiatry 2004 Jul 5: 143-8 |
| PMID | 15346538 |
| Title | Leukocyte elastase and autoantibodies to nerve growth factor in the acute phase of schizophrenia and their relationship to symptomatology. |
| Abstract | Many investigations suggest that abnormalities of the immune system are involved in the pathophysiology of schizophrenia. We recently found increased activity of leukocyte elastase (LE) and elevated levels of autoantibodies to neurospecific protein - nerve growth factor (Aab to NGF) - products of the innate and adaptive arms of the immune system in the serum of patients with acute stage schizophrenia. The aim of this study is to elucidate whether or not the changes of LE activity and Aab to NGF level are related to prominent features of schizophrenia. Patients (n=71) corresponding to ICD-10 criteria for relapse-remitting schizophrenia were assessed by the Positive and Negative Syndrome Scale (PANSS). Patients with predominantly positive symptoms showed significantly elevated serum levels of Aab to NGF compared to patients with predominantly negative symptoms, who were more likely to exhibit the high LE activity. Moreover, progression of positive symptoms was coupled with gradual increase of Aab to NGF level and reduction of LE activity. Based on these findings we conclude that the high levels of Aab to NGF relate to a clinical picture characterised mainly by positive symptoms of schizophrenia, whereas high LE-activities relate to a clinical picture with mainly negative symptoms of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypal |
| 17 | Eur Neuropsychopharmacol 2005 May 15: 319-29 |
| PMID | 15820422 |
| Title | The possible role of neurotrophins in the pathogenesis and therapy of schizophrenia. |
| Abstract | The pathogenesis of schizophrenia may be ascribed to early maldevelopment of brain tissue. Neurotrophins are a group of dimeric proteins that affect the development of the nervous system in all vertebrates' species. Since neurotrophins, as well as other growth factors, play a crucial role in neurodevelopment, they are plausible candidates of taking part in the pathophysiology of schizophrenia. In line with this hypothesis, accumulating preclinical and clinical data indicate that dysfunctions of nerve growth factor (NGF), brain derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3) may contribute to impaired brain development, neuroplasticity and synaptic "dysconnectivity" leading to the schizophrenic syndrome, or at least some of its presentations. This article reviews the functions of neurotrophins in the complex process of normal brain development, and their possible relevance to the neuropathology and neuropharmacology of schizophrenia. Further research in this area may bring about novel pharmacological therapeutic strategies to this chronic debilitating disorder. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypal |
| 18 | Eur Neuropsychopharmacol 2005 May 15: 319-29 |
| PMID | 15820422 |
| Title | The possible role of neurotrophins in the pathogenesis and therapy of schizophrenia. |
| Abstract | The pathogenesis of schizophrenia may be ascribed to early maldevelopment of brain tissue. Neurotrophins are a group of dimeric proteins that affect the development of the nervous system in all vertebrates' species. Since neurotrophins, as well as other growth factors, play a crucial role in neurodevelopment, they are plausible candidates of taking part in the pathophysiology of schizophrenia. In line with this hypothesis, accumulating preclinical and clinical data indicate that dysfunctions of nerve growth factor (NGF), brain derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3) may contribute to impaired brain development, neuroplasticity and synaptic "dysconnectivity" leading to the schizophrenic syndrome, or at least some of its presentations. This article reviews the functions of neurotrophins in the complex process of normal brain development, and their possible relevance to the neuropathology and neuropharmacology of schizophrenia. Further research in this area may bring about novel pharmacological therapeutic strategies to this chronic debilitating disorder. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypal |
| 19 | Zh Nevrol Psikhiatr Im S S Korsakova 2005 -1 105: 45-9 |
| PMID | 16329635 |
| Title | [A state of innate and adaptive immunity in children with schizophrenia and in the high-risk group for the disease]. |
| Abstract | Leukocyte elastase (LE) activity, alpha1-proteinase inhibitor (alpha1-PI), C-reactive protein (CRP) as the indices of innate immunity and the level of autoantibodies to nerve growth factor (Aab-NGF) and to basic myelin protein (Aab-BMP) as the indices of adaptive immunity have been studied in the blood serum of 40 children at high risk for schizophrenia and in 32 children with schizophrenia. In the high-risk group, an increase both of the LE activity, CRP content and variance of alpha1-PI concentrations, indicating the activation of innate immunity, was found. LE activity correlated with severity of schizotypal diathesis. The development of schizophrenic process is accompanied by generalization of the immune response: along with activation of the innate immunity, there was activation of immunity acquired as an increase of the level of autoantibodies to neuroantigenes. It is suggested that activation of innate and adaptive immunity is related to the processes determining the disturbances of the nervous system development. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypal |
| 20 | Zh Nevrol Psikhiatr Im S S Korsakova 2005 -1 105: 45-9 |
| PMID | 16329635 |
| Title | [A state of innate and adaptive immunity in children with schizophrenia and in the high-risk group for the disease]. |
| Abstract | Leukocyte elastase (LE) activity, alpha1-proteinase inhibitor (alpha1-PI), C-reactive protein (CRP) as the indices of innate immunity and the level of autoantibodies to nerve growth factor (Aab-NGF) and to basic myelin protein (Aab-BMP) as the indices of adaptive immunity have been studied in the blood serum of 40 children at high risk for schizophrenia and in 32 children with schizophrenia. In the high-risk group, an increase both of the LE activity, CRP content and variance of alpha1-PI concentrations, indicating the activation of innate immunity, was found. LE activity correlated with severity of schizotypal diathesis. The development of schizophrenic process is accompanied by generalization of the immune response: along with activation of the innate immunity, there was activation of immunity acquired as an increase of the level of autoantibodies to neuroantigenes. It is suggested that activation of innate and adaptive immunity is related to the processes determining the disturbances of the nervous system development. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypal |
| 21 | Zh Nevrol Psikhiatr Im S S Korsakova 2005 -1 105: 45-9 |
| PMID | 16329635 |
| Title | [A state of innate and adaptive immunity in children with schizophrenia and in the high-risk group for the disease]. |
| Abstract | Leukocyte elastase (LE) activity, alpha1-proteinase inhibitor (alpha1-PI), C-reactive protein (CRP) as the indices of innate immunity and the level of autoantibodies to nerve growth factor (Aab-NGF) and to basic myelin protein (Aab-BMP) as the indices of adaptive immunity have been studied in the blood serum of 40 children at high risk for schizophrenia and in 32 children with schizophrenia. In the high-risk group, an increase both of the LE activity, CRP content and variance of alpha1-PI concentrations, indicating the activation of innate immunity, was found. LE activity correlated with severity of schizotypal diathesis. The development of schizophrenic process is accompanied by generalization of the immune response: along with activation of the innate immunity, there was activation of immunity acquired as an increase of the level of autoantibodies to neuroantigenes. It is suggested that activation of innate and adaptive immunity is related to the processes determining the disturbances of the nervous system development. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypal |
| 22 | Neuroscience 2005 -1 130: 997-1012 |
| PMID | 15652996 |
| Title | Repeated nicotine exposure in rats: effects on memory function, cholinergic markers and nerve growth factor. |
| Abstract | A decrease in the number of nicotinic-acetylcholine receptors (nAChRs) in the brain is thought to contribute to the cognitive dysfunction associated with diseases as diverse as Alzheimer's disease and schizophrenia. Interestingly, nicotine and similar compounds have been shown to enhance memory function and increase the expression of nAChRs and therefore, could have a therapeutic role in the aforementioned diseases. Nicotine has also been shown to exert positive effects on certain neurotrophins such as nerve growth factor (NGF), and therefore could play a role beyond mere symptomatic therapy. However, to date, comprehensive studies of nicotine's effects on the expression of specific acetylcholine (ACh) receptor subtypes, key cholinergic proteins (that are regulated by NGF) such as choline acetyltransferase (ChAT) and the vesicular ACh transporter (VAChT) are lacking. Studies to further investigate the effects of nicotine on NGF especially its high- and low-affinity receptors are also needed. In the present study, male Wistar rats exposed a relatively low dosage of nicotine (0.35 mg/kg every 12 h) for 14 days demonstrated improved memory performance (assessed in two separate water maze testing methods) when compared with controls. Autoradiographic experiments indicated that nicotine increased [3H]-epibatidine, [125I]-alpha-bungarotoxin and [3H]-AFDX384, but not [3H]-pirenzepine binding sites in several learning- and memory-related brain areas. The expression of ChAT, VAChT, as well as tropomyosin-receptor kinase A (TrkA) NGF receptors and phospho-TrK receptors was increased by nicotine in the hippocampus. No changes were observed in the levels of the NGF peptide or low affinity p75 neurotrophin receptors (p75NTR), however. These results suggest that repeated exposure to nicotine results in positive effects on central cholinergic markers and memory function, which may be mediated via effects on high-affinity NGF receptors. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypal |
| 23 | Zh Nevrol Psikhiatr Im S S Korsakova 2005 -1 105: 47-51 |
| PMID | 15954212 |
| Title | [Some indices of congenital and acquired immunity in patients with endogenous diseases of schizophrenic spectrum disorders]. |
| Abstract | Indices of congenital leukocyte elastase (LE) activity and adaptive immunity (a level of autoantiboies to nerve growth factor--AabNGF) in blood serum of patients with schizophrenia (attack-like, continuous and slow progressive types) and schizoaffective psychosis have been compared with clinical presentations of the disorders. A patient's state was assessed by clinico-psychopathological methods and with the Positive and Negative Syndromes Scale (PANSS). All schizophrenia types and schizoaffective psychosis were accompanied by LE activity elevation. An increase of AabNGF level was observed only in attack like and continuous schizophrenia. Correlations between AabNGF level and negative symptoms evaluated, using the PANSS, suggest a relation of autoimmune reactions against NGF to the progression of schizophrenic process. Differences in AabNGF level between schizoaffective psychosis and attack-like schizophrenia confirm nosologic independence of schizoaffective psychosis and demand for additional differential laboratory diagnosis of these disorders. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypal |
| 24 | Zh Nevrol Psikhiatr Im S S Korsakova 2005 -1 105: 47-51 |
| PMID | 15954212 |
| Title | [Some indices of congenital and acquired immunity in patients with endogenous diseases of schizophrenic spectrum disorders]. |
| Abstract | Indices of congenital leukocyte elastase (LE) activity and adaptive immunity (a level of autoantiboies to nerve growth factor--AabNGF) in blood serum of patients with schizophrenia (attack-like, continuous and slow progressive types) and schizoaffective psychosis have been compared with clinical presentations of the disorders. A patient's state was assessed by clinico-psychopathological methods and with the Positive and Negative Syndromes Scale (PANSS). All schizophrenia types and schizoaffective psychosis were accompanied by LE activity elevation. An increase of AabNGF level was observed only in attack like and continuous schizophrenia. Correlations between AabNGF level and negative symptoms evaluated, using the PANSS, suggest a relation of autoimmune reactions against NGF to the progression of schizophrenic process. Differences in AabNGF level between schizoaffective psychosis and attack-like schizophrenia confirm nosologic independence of schizoaffective psychosis and demand for additional differential laboratory diagnosis of these disorders. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypal |
| 25 | Med. Hypotheses 2006 -1 67: 354-8 |
| PMID | 16540254 |
| Title | Dopamine D3 receptor and schizophrenia: a widened scope for the immune hypothesis. |
| Abstract | schizophrenia may be related to immunity as is suggested by many findings of altered immune parameters in schizophrenic patients. How immune alterations might be involved in the emergence of psychosis is still unclear. Clearly, however, the dopamine hypothesis has been confirmed in recent studies, which implies a crucial role for dopamine and the dopamine D2 receptor (D2R) within the pathogenesis of schizophrenia. The Dopamine D3 receptor (D3R) is considered to have autoreceptor properties modulating the synthesis and release of dopamine, thereby possibly antagonizing the dopamine D2-receptor-mediated effects of dopamine and has been found reduced in schizophrenic patients during acute psychosis and increasing in the advent of negative schizophrenic symptoms. Immune parameters apparently influence the expression of dopamine receptors by means of their capability to induce regulatory factors involved in the expression of dopamine receptor subtypes, such as the neurotrophins, associations of which with psychosis have been reported repeatedly. Here, we propose a hypothesis of immune alterations that influence the production of distinct neurotrophins such as BDNF and NGF that, as animal studies suggest, influence the expression of dopamine receptor subtypes. This mechanism could result in a decrease of D3R and a consecutive relative preponderance of D2R and thereby connect immune alterations and schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypal |
| 26 | Med. Hypotheses 2006 -1 67: 354-8 |
| PMID | 16540254 |
| Title | Dopamine D3 receptor and schizophrenia: a widened scope for the immune hypothesis. |
| Abstract | schizophrenia may be related to immunity as is suggested by many findings of altered immune parameters in schizophrenic patients. How immune alterations might be involved in the emergence of psychosis is still unclear. Clearly, however, the dopamine hypothesis has been confirmed in recent studies, which implies a crucial role for dopamine and the dopamine D2 receptor (D2R) within the pathogenesis of schizophrenia. The Dopamine D3 receptor (D3R) is considered to have autoreceptor properties modulating the synthesis and release of dopamine, thereby possibly antagonizing the dopamine D2-receptor-mediated effects of dopamine and has been found reduced in schizophrenic patients during acute psychosis and increasing in the advent of negative schizophrenic symptoms. Immune parameters apparently influence the expression of dopamine receptors by means of their capability to induce regulatory factors involved in the expression of dopamine receptor subtypes, such as the neurotrophins, associations of which with psychosis have been reported repeatedly. Here, we propose a hypothesis of immune alterations that influence the production of distinct neurotrophins such as BDNF and NGF that, as animal studies suggest, influence the expression of dopamine receptor subtypes. This mechanism could result in a decrease of D3R and a consecutive relative preponderance of D2R and thereby connect immune alterations and schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypal |
| 27 | Neurosci. Lett. 2006 Jun 400: 262-6 |
| PMID | 16540246 |
| Title | Adequate antipsychotic treatment normalizes serum nerve growth factor concentrations in schizophrenia with and without cannabis or additional substance abuse. |
| Abstract | Neurotrophins such as nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) are important for the development and maintenance of neuron function. Neurodevelopment is thought to be impaired in schizophrenia, and vulnerable schizophrenic brains may be more sensitive to toxic influences. Thus, cannabis as a neurotoxin (and other substances) may be more harmful to schizophrenic brains than to non-schizophrenic brains, when used chronically. In a previous study we demonstrated an earlier disease onset and significantly higher serum NGF concentrations in drug-naïve schizophrenic patients with previous long-term cannabis abuse than in schizophrenics without cannabis abuse or cannabis abusers without schizophrenia. We therefore investigated whether this difference is still observed after treatment. Serum NGF measured in 114 treated schizophrenic patients (schizophrenia alone, n=66; schizophrenia plus cannabis abuse, n=42; schizophrenia plus multiple substance abuse, n=6) no longer differed significantly among those groups and from the control groups (healthy controls, n=51; cannabis controls, n=24; multiple substance controls, n=6). These results were confirmed by an additional prospective study in 28 patients suffering from schizophrenia (S) or schizophrenia with cannabis abuse (SC). Previously elevated serum NGF levels in the drug-naïve state, also differing between the groups (S: 83.44+/-265.25 pg/ml; SC: 246.89+/-310.24 pg/ml, S versus SC: p=0.03) dropped to 10.72+/-14.13 pg/ml (S) and 34.19+/-38.96 pg/ml (SC) (S versus SC, p>0.05), respectively, after adequate antipsychotic treatment. We thus conclude that antipsychotic treatment leads to recovery of neural integrity, as indicated by renormalized NGF values. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypal |
| 28 | Neurosci. Lett. 2006 Jun 400: 262-6 |
| PMID | 16540246 |
| Title | Adequate antipsychotic treatment normalizes serum nerve growth factor concentrations in schizophrenia with and without cannabis or additional substance abuse. |
| Abstract | Neurotrophins such as nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) are important for the development and maintenance of neuron function. Neurodevelopment is thought to be impaired in schizophrenia, and vulnerable schizophrenic brains may be more sensitive to toxic influences. Thus, cannabis as a neurotoxin (and other substances) may be more harmful to schizophrenic brains than to non-schizophrenic brains, when used chronically. In a previous study we demonstrated an earlier disease onset and significantly higher serum NGF concentrations in drug-naïve schizophrenic patients with previous long-term cannabis abuse than in schizophrenics without cannabis abuse or cannabis abusers without schizophrenia. We therefore investigated whether this difference is still observed after treatment. Serum NGF measured in 114 treated schizophrenic patients (schizophrenia alone, n=66; schizophrenia plus cannabis abuse, n=42; schizophrenia plus multiple substance abuse, n=6) no longer differed significantly among those groups and from the control groups (healthy controls, n=51; cannabis controls, n=24; multiple substance controls, n=6). These results were confirmed by an additional prospective study in 28 patients suffering from schizophrenia (S) or schizophrenia with cannabis abuse (SC). Previously elevated serum NGF levels in the drug-naïve state, also differing between the groups (S: 83.44+/-265.25 pg/ml; SC: 246.89+/-310.24 pg/ml, S versus SC: p=0.03) dropped to 10.72+/-14.13 pg/ml (S) and 34.19+/-38.96 pg/ml (SC) (S versus SC, p>0.05), respectively, after adequate antipsychotic treatment. We thus conclude that antipsychotic treatment leads to recovery of neural integrity, as indicated by renormalized NGF values. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypal |
| 29 | Neurosci. Lett. 2006 Jun 400: 262-6 |
| PMID | 16540246 |
| Title | Adequate antipsychotic treatment normalizes serum nerve growth factor concentrations in schizophrenia with and without cannabis or additional substance abuse. |
| Abstract | Neurotrophins such as nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) are important for the development and maintenance of neuron function. Neurodevelopment is thought to be impaired in schizophrenia, and vulnerable schizophrenic brains may be more sensitive to toxic influences. Thus, cannabis as a neurotoxin (and other substances) may be more harmful to schizophrenic brains than to non-schizophrenic brains, when used chronically. In a previous study we demonstrated an earlier disease onset and significantly higher serum NGF concentrations in drug-naïve schizophrenic patients with previous long-term cannabis abuse than in schizophrenics without cannabis abuse or cannabis abusers without schizophrenia. We therefore investigated whether this difference is still observed after treatment. Serum NGF measured in 114 treated schizophrenic patients (schizophrenia alone, n=66; schizophrenia plus cannabis abuse, n=42; schizophrenia plus multiple substance abuse, n=6) no longer differed significantly among those groups and from the control groups (healthy controls, n=51; cannabis controls, n=24; multiple substance controls, n=6). These results were confirmed by an additional prospective study in 28 patients suffering from schizophrenia (S) or schizophrenia with cannabis abuse (SC). Previously elevated serum NGF levels in the drug-naïve state, also differing between the groups (S: 83.44+/-265.25 pg/ml; SC: 246.89+/-310.24 pg/ml, S versus SC: p=0.03) dropped to 10.72+/-14.13 pg/ml (S) and 34.19+/-38.96 pg/ml (SC) (S versus SC, p>0.05), respectively, after adequate antipsychotic treatment. We thus conclude that antipsychotic treatment leads to recovery of neural integrity, as indicated by renormalized NGF values. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypal |
| 30 | Schizophr. Res. 2006 Feb 82: 95-106 |
| PMID | 16442781 |
| Title | Differential effects of long-term treatment with typical and atypical antipsychotics on NGF and BDNF levels in rat striatum and hippocampus. |
| Abstract | The results of mostly short-term treatment studies in human patients and animals suggest that second-generation antipsychotics (SGAs) such as risperidone (RISP) and olanzapine (OLZ) compared to first-generation antipsychotics (FGAs) such as haloperidol (HAL) and chlorpromazine (CPZ) have neuroprotective effects. The animal studies indicate that these effects are probably mediated through increased expression of neurotrophic factors such as nerve growth factor (NGF) and brain derived neurotrophic factor (BDNF). However, since antipsychotics are commonly used for very long-term treatment periods, particularly in schizophrenic patients, it is important to measure the effects of chronic administration of antipsychotic drugs on the aforementioned growth factors. This study determined the effects of 90- and 180-day treatments with two FGAs, HAL and CPZ, and two SGAs, RISP and OLZ, on the levels of NGF and BDNF protein in hippocampus and striatum of rat. Furthermore, since a preliminary study showed that 90-day treatment of HAL caused significant reductions in the expression of both NGF and BDNF the HAL-treated animals were then switched to SGAs for the next 90 days to assess the potential for restoration of trophic factor levels. After the 90-day treatment, NGF levels in the hippocampus were reduced by 60-70% with HAL or CPZ, and by only 25-30% with RISP or OLZ compared to levels with vehicle only. After the 180-day treatment, NGF levels were further reduced with HAL, RISP, and OLZ, but not with CPZ. The magnitude of the NGF decreases in the striatum was larger (70-90%) with all the antipsychotics compared to the hippocampus. However, the pattern of BDNF changes in the hippocampus differed significantly from the striatum after 90- or 180-day treatment with the antipsychotics. In hippocampus, compared to controls, BDNF levels remained unchanged with OLZ both after 90 and 180 days of treatment. Whereas, larger decreases in BDNF levels were observed with HAL or CPZ and intermediate decreases were observed with RISP after 90 days of treatment that continued to decline up to 180 days. Furthermore, switching HAL animals after 90 days of treatment to either RISP or OLZ for the next 90 days significantly restored levels of both NGF and BDNF in both the brain regions. These data indicate that SGAs compared to FGAs induce less deleterious effects on neurotrophic factor levels in the brain and may also offer ability to reverse the more pronounced negative effects of FGAs as well. These data may have significant clinical implications for long-term antipsychotic selection as well as the common practice of antipsychotic switchover. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypal |
| 31 | Neurosci. Res. 2007 Jul 58: 234-44 |
| PMID | 17418909 |
| Title | PC12 cell model of inducible expression of mutant DISC1: new evidence for a dominant-negative mechanism of abnormal neuronal differentiation. |
| Abstract | A balanced chromosomal translocation, segregating with mental illnesses in a large Scottish family, interrupts the disrupted-in-schizophrenia 1 (DISC1) gene, which would result in loss of DISC1 function via haploinsufficiency or dominant-negative effects (or possibly could cause gain-of-function effects) if a truncated protein is present. To evaluate the effects of a predicted protein, mutant DISC1, we generated stable PC12 cell clones with inducible expression of mutant or full-length human DISC1 (hDISC1). Our study presents new observations that the inhibitory effects of mutant hDISC1 on NGF-induced neurite outgrowth are dependent on the level and timing of expression of mutant DISC1 and the concentrations of NGF, and are associated with altered sub-cellular distribution of endogenous DISC1 and ATF4, and decreased protein levels of LIS1. Thus, inducible expression of DISC1 in PC12 cell clones is a valuable in vitro model for further studying the molecular mechanisms likely due to loss of function of DISC1 relevant to the pathogenesis of major mental illnesses. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypal |
| 32 | J. Psychopharmacol. (Oxford) 2007 Nov 21: 820-5 |
| PMID | 17715210 |
| Title | Chronic heroin and cocaine abuse is associated with decreased serum concentrations of the nerve growth factor and brain-derived neurotrophic factor. |
| Abstract | Chronic cocaine and heroin users display a variety of central nervous system (CNS) dysfunctions including impaired attention, learning, memory, reaction time, cognitive flexibility, impulse control and selective processing. These findings suggest that these drugs may alter normal brain functions and possibly cause neurotoxicity. Neurotrophins are a class of proteins that serve as survival factors for CNS neurons. In particular, nerve growth factor (NGF) plays an important role in the survival and function of cholinergic neurons while brain-derived neurotrophic factor (BDNF) is involved in synaptic plasticity and in the maintenance of midbrain dopaminergic and cholinergic neurons. In the present study, we measured by enzyme-linked immunosorbent assay (ELISA) the NGF and BDNF levels in serum of three groups of subjects: heroin-dependent patients, cocaine-dependent patients and healthy volunteers. Our goal was to identify possible change in serum neurotrophins in heroin and cocaine users. BDNF was decreased in heroin users whereas NGF was decreased in both heroin and cocaine users. These findings indicate that NGF and BDNF may play a role in the neurotoxicity and addiction induced by these drugs. In view of the neurotrophin hypothesis of schizophrenia the data also suggest that reduced level of neurotrophins may increase the risk of developing psychosis in drug users. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypal |
| 33 | Eur Neuropsychopharmacol 2007 Dec 17: 756-62 |
| PMID | 17434716 |
| Title | Chronic amphetamine treatment reduces NGF and BDNF in the rat brain. |
| Abstract | Amphetamines (methamphetamine and d-amphetamine) are dopaminergic and noradrenergic agonists and are highly addictive drugs with neurotoxic effect on the brain. In human subjects, it has also been observed that amphetamine causes psychosis resembling positive symptoms of schizophrenia. Neurotrophins are molecules involved in neuronal survival and plasticity and protect neurons against (BDNF) are the most abundant neurotrophins in the central nervous system (CNS) and are important survival factors for cholinergic and dopaminergic neurons. Interestingly, it has been proposed that deficits in the production or utilization of neurotrophins participate in the pathogenesis of schizophrenia. In this study in order to investigate the mechanism of amphetamine-induced neurotoxicity and further elucidate the role of neurotrophins in the pathogenesis of schizophrenia we administered intraperitoneally d-amphetamine for 8 days to rats and measured the levels of neurotrophins NGF and BDNF in selected brain regions by ELISA. Amphetamine reduced NGF levels in the hippocampus, occipital cortex and hypothalamus and of BDNF in the occipital cortex and hypothalamus. Thus the present data indicate that chronic amphetamine can reduce the levels of NGF and BDNF in selected brain regions. This reduction may account for some of the effects of amphetamine in the CNS neurons and provides evidences for the role of neurotrophins in schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypal |
| 34 | Neuroscience 2007 Dec 150: 413-24 |
| PMID | 17942237 |
| Title | Protracted effects of chronic oral haloperidol and risperidone on nerve growth factor, cholinergic neurons, and spatial reference learning in rats. |
| Abstract | The primary therapeutic agents used for schizophrenia, antipsychotic drugs, ameliorate psychotic symptoms; however, their chronic effects on cognition (or the physiologic processes of the brain that support cognition) are largely unknown. The purpose of this rodent study was to extend our previous work on this subject by investigating persistent effects (i.e. during a 14 day drug-free washout period) of chronic treatment (i.e. ranging from 45 days to 6 months) with a representative first and second generation antipsychotic. Drug effects on learning and memory and important neurobiological substrates of memory, the neurotrophin, nerve growth factor (NGF) and its receptors, and certain components of the basal forebrain cholinergic system were investigated. Behavioral effects of oral haloperidol (2.0 mg/kg/day), or risperidone (2.5 mg/kg/day) were assessed in an open field, a water maze task, and a radial arm maze procedure and neurochemical effects in brain tissue were subsequently measured by enzyme-linked immunosorbent assays (ELISAs). The results indicated that both antipsychotics produced time-dependent and protracted deficits in the performance of a water maze procedure when compared with vehicle-treated controls, while neither drug was associated with significant alterations in radial arm maze performance. Interestingly, haloperidol, but not risperidone, was detectible in the rodent brain in appreciable levels for up to 2 weeks after drug discontinuation. Both antipsychotics were also associated with reduced levels of NGF protein in the basal forebrain and prefrontal cortex and significant (or nearly significant) decreases in phosphorylated tropomyosin-receptor kinase A (TrkA) protein and the vesicular acetylcholine transporter (depending on the brain region analyzed). Neither antipsychotic markedly affected TrkA or p75 neurotrophin receptor levels. These data in rats indicate that chronic treatment with either haloperidol or risperidone may be associated with protracted negative effects on cognitive function as well as important neurotrophin and neurotransmitter pathways that support cognition. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypal |
| 35 | Neurosci. Lett. 2008 Sep 442: 100-3 |
| PMID | 18638525 |
| Title | Distinct regulation of brain-derived neurotrophic factor and noradrenaline in S100B knockout mice. |
| Abstract | The mainly glia-derived protein S100B has been shown to be involved in the pathophysiology of diseases such as neurodegenerative diseases, schizophrenia or depression. These diseases go along with distinct changes of cerebral neurotransmitters and neurotrophic factors. Few and partly inconsistent data exist on the influence of cerebral S100B protein levels on different neurotransmitters. Therefore we investigated levels of serotonin (5-HT) and its metabolite 5-hydroxyindoleacetic acid (5-HIAA), noradrenaline (NA), dopamine (DA), brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) in the hippocampus, frontal cortex and residual neocortex in S100B knock out (S100B KO) mice compared to wildtype controls. There was a significant increase of hippocampal BDNF (+53%) and a decrease of hippocampal (-12%) and residual neocortical (-15%) NA in 10-month-old S100B KO mice compared to wildtype mice whereas the other mediators investigated did not show genotype-dependent changes. The increased hippocampal BDNF may represent an endogenous attempt to compensate trophic effects of S100B protein especially on serotonergic neurons, which have been shown to be unaffected in S100B KO mice previously. As referred to changes in NA levels functional studies are warranted to elucidate the link between S100B protein and the noradrenergic metabolism. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypal |
| 36 | Metab Brain Dis 2008 Jun 23: 213-9 |
| PMID | 18496748 |
| Title | Lack of effect of antipsychotics on BNDF and NGF levels in hippocampus of Wistar rats. |
| Abstract | schizophrenia is a common and serious mental disorder, in which the majority of patients require long-term antipsychotic treatment. Several studies have suggested that schizophrenia is associated with decreased neurotrophins such as brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF). Investigation of the mechanisms of pharmacological agents that are used in the treatment of schizophrenia has been used to better understand the basis of the pathology associated with this mental illness. The present study aims to investigate the effect of chronic treatment with antipsychotics, named haloperidol (HAL), clozapine (CLO), olanzapine (OLZ) or aripiprazole (ARI) on BDNF and NGF levels in rat hippocampus. Adult male Wistar rats received daily injections of HAL (1.5 mg/kg), CLO (25 mg/kg), OLZ (2.5, 5 or 10 mg/kg) or ARI (2, 10 or 20 mg/kg), whereas control animals were given vehicle. BDNF and NGF levels were measured in rat hippocampus by sandwich-ELISA. The results showed that chronic administration of antipsychotics did not modify BDNF and NGF levels in rat hippocampus, suggesting that their therapeutic properties are not mediated by stimulation of these neurotrophins. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypal |
| 37 | Med Chem 2008 May 4: 256-63 |
| PMID | 18473918 |
| Title | Expression of mRNA of neurotrophic factors and their receptors are significantly altered after subchronic ketamine treatment. |
| Abstract | The neurotrophic factors play an important role in the maintenance of neurone viability and neuronal communication which are considered to be altered in schizophrenia. Subchronic application of ketamine (Ket) was found to be a useful model in schizophrenia research. To further validate this model the mRNA levels of neurotrophic factors NGF, NT-3, and BDNF and their receptors TrkA, TrkB, and TrkC, respectively, were measured in different brain areas in Ket-pretreated rats subchronically dosed with the atypical antipsychotic drug risperidone (Ris). With the exception of NGF in the frontal cortex, Ket pretreatment did change NGF, NT-3, and BDNF mRNA levels in the frontal cortex, the hippocampus, the striatum, the thalamus/hypothalamus region, and in the cerebellum. These changes correspond with changes at their tyrosine kinase receptors. Ris treatment normalised altered NT-3 levels in the hippocampus and balanced BDNF levels in the same structure. It was concluded that the Ket model might reflect distinct alterations in neurotrophic factor activity as found in schizophrenic patients and, moreover, that Ris treatment rebalances disturbed neurotrophic factor activity. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypal |
| 38 | Med Chem 2008 May 4: 256-63 |
| PMID | 18473918 |
| Title | Expression of mRNA of neurotrophic factors and their receptors are significantly altered after subchronic ketamine treatment. |
| Abstract | The neurotrophic factors play an important role in the maintenance of neurone viability and neuronal communication which are considered to be altered in schizophrenia. Subchronic application of ketamine (Ket) was found to be a useful model in schizophrenia research. To further validate this model the mRNA levels of neurotrophic factors NGF, NT-3, and BDNF and their receptors TrkA, TrkB, and TrkC, respectively, were measured in different brain areas in Ket-pretreated rats subchronically dosed with the atypical antipsychotic drug risperidone (Ris). With the exception of NGF in the frontal cortex, Ket pretreatment did change NGF, NT-3, and BDNF mRNA levels in the frontal cortex, the hippocampus, the striatum, the thalamus/hypothalamus region, and in the cerebellum. These changes correspond with changes at their tyrosine kinase receptors. Ris treatment normalised altered NT-3 levels in the hippocampus and balanced BDNF levels in the same structure. It was concluded that the Ket model might reflect distinct alterations in neurotrophic factor activity as found in schizophrenic patients and, moreover, that Ris treatment rebalances disturbed neurotrophic factor activity. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypal |
| 39 | Ann. Ist. Super. Sanita 2008 -1 44: 167-77 |
| PMID | 18660566 |
| Title | Clozapine or Haloperidol in rats prenatally exposed to methylazoxymethanol, a compound inducing entorhinal-hippocampal deficits, alter brain and blood neurotrophins' concentrations. |
| Abstract | Rats exposed during prenatal life to methylazoxymethanol (MAM) display in postnatal age structural and behavioral deficits resembling those observed in schizophrenic patients. These deficits are associated with significant changes in brain nerve growth factor (NGF) and brain derived neurotrophic factor (BDNF), particularly in the hippocampus and entorhinal cortex. In the present study, we used the MAM model to investigate in young rats the effect of antipsychotics, Clozapine and Haloperidol, on brain and blood NGF and BDNF presence. Young animals were used because administration of antipsychotics during adolescence is a common feature of intervention. The results showed that administration of Clozapine and Haloperidol causes significant changes in the concentration of NGF and BDNF in the brain and bloodstream of MAM-treated rats. These findings indicate that these drugs may affect the synthesis and release of neurotrophins in the central nervous system and in the blood circulation. In addition, the MAM model can be a useful tool to investigate the biochemical and molecular mechanisms regarding the effects of antipsychotics. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypal |
| 40 | J. Neurochem. 2008 Mar 104: 1450-65 |
| PMID | 18028338 |
| Title | Cholecystokinin-2 receptor mediated gene expression in neuronal PC12 cells. |
| Abstract | Cholecystokinin (CCK) is abundantly expressed in the CNS, in which it regulates feeding behavior and long-term memory. Moreover, CCK has been implicated in mental disorders, such as anxiety and schizophrenia. Despite its manifest physiological and pathophysiological role, the molecular targets of neuronal CCK are incompletely understood. To identify genes regulated by neuronal CCK, we generated neuronal PC12 cells stably expressing the CCK-2 receptor (CCK-2R) and treated the cells with sulphated CCK-8 for 2-16 h, before the global expression profile was examined. The changes in gene expression peaked after 2 h, with 67 differentially expressed transcripts identified. A pathway analysis indicated that CCK was implicated in the regulation of the circadian clock system, the plasminogen system and cholesterol metabolism. But transcripts encoding proteins involved in dopamine signaling, ornithine decarboxylase (ODC) regulation, memory and epidermal growth factor receptor (EGFR) signaling were also found. Several target genes contained cAMP response elements (CREs), serum response elements (SREs), activator protein 1 (AP1) elements and GC-rich regions, but otherwise no common regulatory promoter element could be identified. Comparison with forskolin- and nerve growth factor (NGF)-treated PC12 cells showed that CCK induced a separate set of target genes. Taken together, we propose that neuronal CCK may have a role in the regulation of the circadian rhythm, the metabolism of cerebral cholesterol and in the regulation of the plasminogen system. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypal |
| 41 | Schizophr Bull 2008 Jan 34: 127-36 |
| PMID | 17525084 |
| Title | Injections of NGF into neonatal frontal cortex decrease social interaction as adults: a rat model of schizophrenia. |
| Abstract | Injection of nerve growth factor (NGF) into the developing frontal cortex (FC) has been shown to produce adult-onset subcortical dopaminergic hyperactivity, impaired prepulse inhibition of the acoustic startle response, and several neuropathological features of schizophrenia. The present study was to determine whether such lesions would lead to impaired social interaction, a prominent negative feature of schizophrenia. Rat pups received daily injections of human recombinant NGF into the developing FC on postnatal days 1 and 2 to partially lesion subplate neurons. Lesioned rats were tested in similar-treatment pairings lasting 23.5 hours using the EthoVision behavioral monitoring system at 6 and 14 weeks of age. Brains were then perfusion fixed for histological analysis. Lesioned rats showed significantly increased movement, relative to controls, during the light phase at 6 weeks of age. At 14 weeks, they maintained a significantly greater mean distance apart from one another, and engaged in significantly less approach and avoidance behavior during the dark phase, relative to controls. Histological changes were consistent with those described previously in this animal model. Results indicate that injections of NGF into the developing FC of neonatal rats result in reduced social interaction, which is consistent with behaviors observed in human schizophrenia patients. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypal |
| 42 | Turk Psikiyatri Derg 2009 -1 20: 175-82 |
| PMID | 19504368 |
| Title | [New pharmacological approaches to the treatment of schizophrenia]. |
| Abstract | schizophrenia is a serious mental disorder with a challenging rational pharmacotherapy. Neurochemical transmission in the dopaminergic system, especially via D2 receptors, and related changes in postsynaptic signal transduction are very important in both the formation of schizophrenia and current pharmacotherapeutic treatment with antipsychotic drugs. Blocking the serotonergic 5-HT2A and 5-HT2C receptors is growing growing importance with regard to the action mechanisms of new generation antipsychotic medications. Recent preclinical and clinical data show that dysfunction of central neurotrophins, such as nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), and neurophin-3 (NT-3) might contribute to impaired brain development and neuroplasticity, leading to schizophrenia. In addition, some recent studies suggest that there is an important relationship between alcohol and substance addiction, and schizophrenia. There is also some preclinical data indicating that the central nitrergic system and agmatine(3/4)a biologically active agent produced after decarboxylation of arginine(3/4)might be interesting and important targets for understanding the etiopathogenesis of schizophrenia and for development of new drugs. Selective dopamine D3 receptor antagonists, specific agonists for metabotropic and NMDA receptors of the glutamatergic system, and nicotinic alpha-7 receptor agonists were reported in preclinical and a limited number of clinical studies as potential new targets for schizophrenia treatment. In this review, new advances in the pharmacotherapy of schizophrenia and possible new targets are discussed in the light of the current literature. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypal |
| 43 | Neuropsychobiology 2009 -1 59: 51-8 |
| PMID | 19270464 |
| Title | Increased plasma brain-derived neurotropic factor, not nerve growth factor-Beta, in schizophrenia patients with better response to risperidone treatment. |
| Abstract | Some neurotropins, including brain-derived neurotropic factor (BDNF) or nerve growth factor-beta (beta-NGF), play important roles in neurodevelopment and neuroprotection. We examined the plasma levels of these 2 factors in schizophrenia patients at the time of admission and after 6 weeks of treatment with risperidone. Plasma BDNF and beta-NGF levels were measured in 36 schizophrenia patients and 36 healthy controls. All the patients underwent 6 weeks of treatment with risperidone. The severity of schizophrenia and response to treatment were assessed with the positive and negative syndrome scale (PANSS). We compared plasma BDNF and beta-NGF levels among much-improved (n = 13, 36.1%, > or =50% PANSS score reduction), minimal-improved (n = 15, 41.7%, > or =25% and <50% PANSS score reduction) and nonresponse patients (n = 8, 22.2%, <25% PANSS score reduction). At baseline, plasma BDNF had no significant difference between schizophrenia patients and controls, but beta-NGF levels were significantly lower in schizophrenia patients than controls (p = 0.037). Plasma BDNF and beta-NGF in all schizophrenia patients had no significant changes between pre- and posttreatment. Baseline BDNF levels were significantly lower in nonresponse patients than others (p = 0.038). After treatment, much-improved patients had significantly higher plasma BDNF than nonresponse patients (p = 0.023). However, beta-NGF levels had no significant differences between them. Our data suggest that higher plasma BDNF levels might be associated with better response to risperidone treatment, while plasma beta-NGF levels might have no effect on the clinical response in schizophrenia patients. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypal |
| 44 | Schizophr. Res. 2009 Dec 115: 209-14 |
| PMID | 19713082 |
| Title | Reduced cerebrospinal fluid and plasma nerve growth factor in drug-naïve psychotic patients. |
| Abstract | Impaired expression and function of several major neurotrophic factors such as nerve growth factor (NGF) has been proposed to contribute to the neurodevelopmental pathology of schizophrenia. However, the evidence in the majority of studies is based on variable and inconsistent levels of plasma NGF in diverse populations of early psychosis or medicated patients with chronic schizophrenia. We report here the first study comparing NGF levels in cerebrospinal fluid (CSF) and plasma from a unique patient cohort (unmedicated, early psychotic patients with similar racial and dietary patterns) and matched healthy controls. Significantly lower levels of NGF in both CSF (p=0.038) and plasma (p=0.002) were observed in drug-naïve first-episode psychosis patients as compared to controls. The levels of NGF in the CSF correlated (p=0.05) to the plasma values in controls. The data on plasma NGF confirm the reported deficits of NGF in drug-naïve first-episode psychosis. The reduced levels first time observed here may have important implications to repeatedly reported neurobiological and clinical deficits which are discussed. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypal |
| 45 | Zh Nevrol Psikhiatr Im S S Korsakova 2009 -1 109: 46-9 |
| PMID | 19672227 |
| Title | [Dynamics of immunological and clinical parameters in the treatment of childhood schizophrenia]. |
| Abstract | A state of innate and adaptive immunity (leukocyte elastase (LE) activity, alpha(1)-proteinase inhibitor (alpha(1)-PI), the level of autoantibodies to nerve growth factor (Aab-NGF) and to basic myelin protein), have been studied in the blood serum of children with schizophrenia and compared to the changes of their clinical-psychopathological state. It has been shown that the exacerbation of schizophrenic process with early onset is accompanied by the activation of some parameters of innate immunity. But the higher activity of LE and alpha(1)-PI before the treatment cannot be considered as a predictive marker of therapeutic efficacy. At the same time, the decrease of LE activity during the treatment is a significant predictor of favorable therapeutic response. The unchanged level of Aab-NGF comparing to controls is also a favorable factor associated with therapeutic efficacy. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypal |
| 46 | Zh Nevrol Psikhiatr Im S S Korsakova 2009 -1 109: 46-9 |
| PMID | 19672227 |
| Title | [Dynamics of immunological and clinical parameters in the treatment of childhood schizophrenia]. |
| Abstract | A state of innate and adaptive immunity (leukocyte elastase (LE) activity, alpha(1)-proteinase inhibitor (alpha(1)-PI), the level of autoantibodies to nerve growth factor (Aab-NGF) and to basic myelin protein), have been studied in the blood serum of children with schizophrenia and compared to the changes of their clinical-psychopathological state. It has been shown that the exacerbation of schizophrenic process with early onset is accompanied by the activation of some parameters of innate immunity. But the higher activity of LE and alpha(1)-PI before the treatment cannot be considered as a predictive marker of therapeutic efficacy. At the same time, the decrease of LE activity during the treatment is a significant predictor of favorable therapeutic response. The unchanged level of Aab-NGF comparing to controls is also a favorable factor associated with therapeutic efficacy. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypal |
| 47 | Zh Nevrol Psikhiatr Im S S Korsakova 2009 -1 109: 44-6 |
| PMID | 19365391 |
| Title | [MRI-parameters of frontal lobes in schizophrenia: correlations with the level of autoantibodies to nerve growth factor in the blood serum]. |
| Abstract | The relationship between MRI-parameters of frontal lobes and levels of autoantibodies to nerve growth factor (Aab-NGF) in the blood serum of patients with schizophrenia and their relatives was studied. The negative correlation between the Aab-NGF level and the total volume of frontal lobes (r= -0,59; p<0,01) was found in the group of patients. No significant correlations were found in the control groups of healthy subjects without family history of schizophrenia and relatives of patients. The authors concede that Aab-NGF may play a substantial role in the development of neuromorphological changes in schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypal |
| 48 | Eur Arch Psychiatry Clin Neurosci 2010 Mar 260: 151-62 |
| PMID | 19579000 |
| Title | Risperidone and haloperidol promote survival of stem cells in the rat hippocampus. |
| Abstract | Altered neuroplasticity contributes to the pathophysiology of schizophrenia. However, the idea that antipsychotics may act, at least in part, by normalizing neurogenesis has not been consistently supported. Our study seeks to determine whether hippocampal cell proliferation is altered in adult rats pretreated with ketamine, a validated model of schizophrenia, and whether chronic administration with neuroleptic drugs (haloperidol and risperidone) affect changes of cell genesis/survival. Ketamine per se has no effect on cell proliferation. Its withdrawal, however, significantly induced cell proliferation/survival in the hippocampus. Risperidone and haloperidol supported cell genesis/survival as well. During ketamine withdrawal, however, their application did not affect cell proliferation/survival additionally. TUNEL staining indicated a cell-protective potency of both neuroleptics with respect to a ketamine-induced cell death. As RT-PCR and Western blot revealed that the treatment effects of risperidone and haloperidol seemed to be mediated through activation of VEGF and MMP2. The mRNA expression of NGF, BDNF, and NT3 was unaffected. From the respective receptors, only TrkA was enhanced when ketamine withdrawal was combined with risperidone or haloperidol. Risperidone also induced BCL-2. Ketamine withdrawal has no effect on the expression of VEGF, MMP2, or BCL-2. It activated the expression of BDNF. This effect was normalized by risperidone or haloperidol. The findings indicate a promoting effect of risperidone and haloperidol on survival of young neurons in the hippocampus by enhancing the expression of the anti-apoptotic protein BCL-2 and by activation of VEGF/MMP2, whereby an interference with ketamine and thus a priority role of the NMDA system was not evident. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypal |
| 49 | Mol. Psychiatry 2010 Aug 15: 778, 798-809 |
| PMID | 20479754 |
| Title | DISC1 regulates cell-cell adhesion, cell-matrix adhesion and neurite outgrowth. |
| Abstract | Disrupted-in-schizophrenia 1 (DISC1) is a promising susceptibility gene for major mental illness. Recent studies have implicated DISC1 in key neurodevelopmental processes, including neurite outgrowth, neuronal migration and proliferation. Here, we report that DISC1 regulates cell-cell and cell-matrix adhesion and neurite outgrowth. DISC1 overexpression increased expression of the adherence junction protein N-cadherin and enhanced cell-cell adhesion. The increased N-cadherin accumulated in the areas of cell-cell contact. DISC1 overexpression also enhanced cell-matrix adhesion by inducing expression of beta1-integrin protein. In the presence of nerve growth factor (NGF), DISC1 overexpression increased beta1-integrin expression at the cell membrane and growth cone. NGF-induced neurite extension was enhanced by DISC1, and anti-beta1-integrin antibody reduced the neurite outgrowth of DISC1-overexpressing cells to the control level. Furthermore, DISC1 also regulated N-cadherin and beta1-integrin expression at the cell membrane in primary neurons. We conclude that DISC1 regulates cell-cell adhesion and cell-matrix adhesion by regulating the expression of adhesion molecules. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypal |
| 50 | Schizophr. Res. 2010 Jun 119: 34-9 |
| PMID | 20303241 |
| Title | Reduced NGF serum levels and abnormal P300 event-related potential in first episode schizophrenia. |
| Abstract | Nerve growth factor (NGF) plays a crucial role in central nervous system neuron plasticity. Low levels of serum NGF in schizophrenic patients suggest that the neurotrophin contributes to the pathogenesis of the disease. NGF is also thought to alter characteristics of event-related brain potential (ERP) components. The auditory-evoked P300 ERP component, considered an index of brain activity, has reduced amplitude in acute and chronic schizophrenia. This study evaluated the relationship among serum NGF levels, P300 characteristics, and Positive and Negative Symptom Scale (PANSS) scores in first episode, neuroleptic naive schizophrenic patients (N=30) and healthy controls (N=28). Serum NGF was measured by ELISA and P300 elicited using auditory oddball paradigm. Compared to control subjects, schizophrenic patients had significantly reduced serum NGF (p<0.001) and lower P300 amplitudes at Fz (p=0.003). Additionally, there was a positive correlation between serum NGF serum and P300 amplitude at Fz. No correlation was found between serum NGF or P300 characteristics and PANSS scores. These results suggest that the effects of NGF in schizophrenia are related not only to regulation of neurodevelopment, but also to the electrophysiological characteristics of nerve growth factor. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypal |
| 51 | Schizophr. Res. 2010 Jun 119: 34-9 |
| PMID | 20303241 |
| Title | Reduced NGF serum levels and abnormal P300 event-related potential in first episode schizophrenia. |
| Abstract | Nerve growth factor (NGF) plays a crucial role in central nervous system neuron plasticity. Low levels of serum NGF in schizophrenic patients suggest that the neurotrophin contributes to the pathogenesis of the disease. NGF is also thought to alter characteristics of event-related brain potential (ERP) components. The auditory-evoked P300 ERP component, considered an index of brain activity, has reduced amplitude in acute and chronic schizophrenia. This study evaluated the relationship among serum NGF levels, P300 characteristics, and Positive and Negative Symptom Scale (PANSS) scores in first episode, neuroleptic naive schizophrenic patients (N=30) and healthy controls (N=28). Serum NGF was measured by ELISA and P300 elicited using auditory oddball paradigm. Compared to control subjects, schizophrenic patients had significantly reduced serum NGF (p<0.001) and lower P300 amplitudes at Fz (p=0.003). Additionally, there was a positive correlation between serum NGF serum and P300 amplitude at Fz. No correlation was found between serum NGF or P300 characteristics and PANSS scores. These results suggest that the effects of NGF in schizophrenia are related not only to regulation of neurodevelopment, but also to the electrophysiological characteristics of nerve growth factor. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypal |
| 52 | Int. J. Neuropsychopharmacol. 2010 Jul 13: 799-805 |
| PMID | 20059802 |
| Title | Chronic antipsychotic treatment: protracted decreases in phospho-TrkA levels in the rat hippocampus. |
| Abstract | There is growing evidence of neurotrophin alterations in neuropsychiatric illnesses such as schizophrenia and further, neurotransmitters known to be adversely affected in schizophrenia (e.g. dopamine) can activate neurotrophin signalling pathways via G protein-coupled receptors. However, it is unclear how the primary therapeutic agents used in schizophrenia affect neurotrophin signalling. This is important given that all currently prescribed antipsychotic drugs serve as ligands at dopamine receptors. In this study, chronic effects of representative conventional and second-generation antipsychotics on nerve growth factor (NGF) receptor levels were assessed in the rat. The results indicated no significant drug effects on TrkA levels in any brain region analysed; however, three of the five antipsychotics analysed significantly decreased phospho-TrkA (i.e. the activated form of the receptor) in the hippocampus. These data indicate that chronic antipsychotic treatment may result in deleterious effects on neurotrophin signalling in an important brain region for information processing and cognition. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypal |
| 53 | Cent Nerv Syst Agents Med Chem 2010 Sep 10: 180-206 |
| PMID | 20528766 |
| Title | Diversity and variability of the effects of nicotine on different cortical regions of the brain - therapeutic and toxicological implications. |
| Abstract | Nicotine/nicotine agonists or allosteric modulators of nicotine receptors have been suggested as the most important therapeutic agents in the prevention and clinical control of cognitive impairment which characterize neuropsychiatric and neurodegenerative disorders such as schizophrenia, attention deficit/hyperactivity disorder and Alzheimer's disease. Both clinical studies and animal experiments support the important role of the nicotinic systems in learning, different kind of memory and cognition. For development of nicotinic treatments we have a well characterized lead compound, nicotine. However, the neural nicotinic mechanisms underlying cognitive functions are not well known because the side effects of nicotine overdose have hindered the development of this therapeutical line. The new development of non-toxic, brain specific nicotine drugs need a full knowledge of these mechanism and a reevaluation of the nicotine effects. This review aims to analyze the different kind of effects of nicotine on the Central Nervous System (CNS), especially on the cortex and hippocampus. Nicotine effects are, theoretically and/or practically, of variable character depending on daily dose and time of treatment; on the subtype and density of the different nicotinic receptors existing in the distinct brain regions; on the processes of desensitization and tolerance of nicotinic receptors and on other neuronal factors. Nicotine produces the above mentioned activation of the cognitive functions acting directly or indirectly on cortical neurons. In some experiments, high doses of nicotine can impair memory. This substance induces increases in the glycolytic pathway and Krebs cycle of neurons, as well as brain blood flow. Nicotine also produces an increase in NGF immunoreactivity in frontoparietal cortex. All these neuronal changes may cause different positive effects such as neuroprotection, neuroplasticity and better performance of synaptic circuits. The benefit of other neuronal changes can be matter of discussion such as some modifications in synaptic transmission, the COX-2 increase in frontoparietal cortex and hippocampus or the changes in the antioxidant systems. Finally, other neuronal changes can be of negative effect such as the induction of apoptosis and oxidative stress (DNA damage, ROS and lipid peroxide increase). All these described effects explain both the beneficial and neurotoxic consequences of the activation of the nicotinic receptors. The diversity and variability of the nicotinic effects should take into account when nicotine agonists will be used as a possible cognitive treatment. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypal |
| 54 | Brain Res. 2011 Mar 1377: 32-40 |
| PMID | 21211516 |
| Title | Potentiation of NGF-induced neurite outgrowth in PC12 cells by papaverine: role played by PLC-?, IP3 receptors. |
| Abstract | Papaverine, an inhibitor of phosphodiesterase (PDE) 10A, is gaining attention for its potential in the treatment of neuropsychiatric diseases such as schizophrenia. However, the precise mechanisms underlying the putative neuroprotective/neurotrophic actions of papaverine remain unclear. Thus, we investigated the effects of papaverine on nerve growth factor (NGF)-induced neurite outgrowth in PC12 cells. Papaverine potentiated NGF-induced neurite outgrowth in PC12 cells in a concentration-dependent manner. In contrast, the selective PDE10A inhibitor MP-10 had no effect on NGF-induced neurite outgrowth. The potentiation of NGF-induced neurite outgrowth by papaverine was blocked by the PLC-? inhibitor U73122. Furthermore, papaverine's potentiation of NGF-induced neurite outgrowth was also blocked by the co-administration of inositol 1,4,5-trisphosphate (IP(3)) receptor antagonists (xestospongin C and 2-aminoethoxydiphenyl borate (2-APB)) and by reduced expression of IP(3) receptor gene (i.e., itpr1 and itpr3) by siRNA. Our findings suggest that papaverine could potentiate NGF-induced neurite outgrowth, and that activation of PLC-? and IP(3) receptors might be involved in the mechanism underlying papaverine's potentiation of neurite outgrowth in PC12 cells. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypal |
| 55 | Psychiatry Res 2011 Aug 189: 72-6 |
| PMID | 21277636 |
| Title | The role of NGF and IL-2 serum level in assisting the diagnosis in first episode schizophrenia. |
| Abstract | Development of reliable diagnostic bio-markers for schizophrenia remains a diagnostic challenge. Serum NGF and IL-2 were analyzed to examine the diagnostic efficiency and predictive capability of these two biomarkers in relation to schizophrenia diagnosis. Thirty neuroleptic naïve subjects with first-episode schizophrenia, thirty patients with major depressive disorder (MDD) and twenty-eight healthy control subjects participated in the study. One-way ANOVA demonstrated significantly lower serum IL-2 and NGF among schizophrenic patients and patients with MDD compared with healthy controls. Receiver operating characteristic (ROC) curve analysis was used to ascertain diagnostic efficiency of serum IL-2 and NGF levels. Area under the ROC curve (AUC) revealed a high level of differentiation between schizophrenic patients and healthy controls for both IL-2 and NGF serum concentrations. Diagnostic efficiency of combined NGF and IL-2 serum levels was also high in schizophrenic patients compared with healthy controls. Serum NGF and IL-2 are promising as potential screening or diagnostic biomarkers for schizophrenia and may be a useful adjunct for clinical assessment. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypal |
| 56 | Psychiatry Res 2011 Aug 189: 72-6 |
| PMID | 21277636 |
| Title | The role of NGF and IL-2 serum level in assisting the diagnosis in first episode schizophrenia. |
| Abstract | Development of reliable diagnostic bio-markers for schizophrenia remains a diagnostic challenge. Serum NGF and IL-2 were analyzed to examine the diagnostic efficiency and predictive capability of these two biomarkers in relation to schizophrenia diagnosis. Thirty neuroleptic naïve subjects with first-episode schizophrenia, thirty patients with major depressive disorder (MDD) and twenty-eight healthy control subjects participated in the study. One-way ANOVA demonstrated significantly lower serum IL-2 and NGF among schizophrenic patients and patients with MDD compared with healthy controls. Receiver operating characteristic (ROC) curve analysis was used to ascertain diagnostic efficiency of serum IL-2 and NGF levels. Area under the ROC curve (AUC) revealed a high level of differentiation between schizophrenic patients and healthy controls for both IL-2 and NGF serum concentrations. Diagnostic efficiency of combined NGF and IL-2 serum levels was also high in schizophrenic patients compared with healthy controls. Serum NGF and IL-2 are promising as potential screening or diagnostic biomarkers for schizophrenia and may be a useful adjunct for clinical assessment. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypal |
| 57 | Psychiatr Danub 2012 Sep 24 Suppl 1: S95-9 |
| PMID | 22945197 |
| Title | The differences between typical and atypical antipsychotics: the effects on neurogenesis. |
| Abstract | Recently, the pharmacological division between typical and atypical antipsychotics has been called into question. New evidence, however, continues to emerge showing differences between these two classes of drugs. Hence typical and atypical antipsychotics are clearly different classes of drugs, as evidenced by their actions, mechanisms, effects and side effects. The most recently investigated field in which both classes of drugs have opposing effects is neuron survival and neurogenesis. schizophrenia has been found to be a disease of progressive reductions in grey matter, and the more lost, the worse the outcome. Medication naive patients have lowered levels of neurotrophins e.g. NT-3, NGF BDNF. The antipsychotic drugs alter the levels of these neurotrophins. Haloperidol, of the typical antipsychotics, causes neuron apoptosis by a free radical induced mechanism, involving Bcl-XS, P53, cytochrome c translocation and caspase 3 activation. Haloperidol also lowers BDNF levels, reducing neuroprotection in the brain to enable haloperidol's toxic effects. Atypical drugs have opposing effects. They increase levels of BDNF, improve cell survival and enhance neurogenesis. Atypical drugs can also prevent or reverse the effects of haloperidol induced toxicity. The mechanism involves the inverse agonism of 5HT receptors, particularly those of the 2A subset, but the situation is considerably more complicated. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypal |
| 58 | J. Neurosci. 2012 Apr 32: 5964-72 |
| PMID | 22539856 |
| Title | Relationship of a variant in the NTRK1 gene to white matter microstructure in young adults. |
| Abstract | The NTRK1 gene (also known as TRKA) encodes a high-affinity receptor for NGF, a neurotrophin involved in nervous system development and myelination. NTRK1 has been implicated in neurological function via links between the T allele at rs6336 (NTRK1-T) and schizophrenia risk. A variant in the neurotrophin gene, BDNF, was previously associated with white matter integrity in young adults, highlighting the importance of neurotrophins to white matter development. We hypothesized that NTRK1-T would relate to lower fractional anisotropy in healthy adults. We scanned 391 healthy adult human twins and their siblings (mean age: 23.6 ± 2.2 years; 31 NTRK1-T carriers, 360 non-carriers) using 105-gradient diffusion tensor imaging at 4 tesla. We evaluated in brain white matter how NTRK1-T and NTRK1 rs4661063 allele A (rs4661063-A, which is in moderate linkage disequilibrium with rs6336) related to voxelwise fractional anisotropy-a common diffusion tensor imaging measure of white matter microstructure. We used mixed-model regression to control for family relatedness, age, and sex. The sample was split in half to test reproducibility of results. The false discovery rate method corrected for voxelwise multiple comparisons. NTRK1-T and rs4661063-A correlated with lower white matter fractional anisotropy, independent of age and sex (multiple-comparisons corrected: false discovery rate critical p = 0.038 for NTRK1-T and 0.013 for rs4661063-A). In each half-sample, the NTRK1-T effect was replicated in the cingulum, corpus callosum, superior and inferior longitudinal fasciculi, inferior fronto-occipital fasciculus, superior corona radiata, and uncinate fasciculus. Our results suggest that NTRK1-T is important for developing white matter microstructure. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypal |
| 59 | Transl Psychiatry 2012 -1 2: e170 |
| PMID | 23047241 |
| Title | Neurite outgrowth mediated by the heat shock protein Hsp90?: a novel target for the antipsychotic drug aripiprazole. |
| Abstract | Aripiprazole is an atypical antipsychotic drug approved for the treatment of psychiatric disorders such as schizophrenia, bipolar disorder, major depressive disorder and autism. The drug shows partial agonistic activity at dopamine D(2) receptors and 5-hydroxytryptamine (5-HT) 5-HT(1A) receptors, and antagonistic activity at 5-HT(2A) receptors. However, the precise mechanistic pathways remain unclear. In this study, we examined the effects of aripiprazole on neurite outgrowth. Aripiprazole significantly potentiated nerve growth factor (NGF)-induced neurite outgrowth in PC12 cells, in a concentration-dependent manner. The 5-HT(1A) receptor antagonist WAY-100635, but not the dopamine D(2) receptor antagonist sulpiride, blocked the effects of aripiprazole, although, only partially. Specific inhibitors of inositol 1,4,5-triphosphate (IP(3)) receptors and BAPTA-AM, a chelator of intracellular Ca(2+), blocked the effects of aripiprazole. Moreover, specific inhibitors of several common signaling pathways phospholipase C-? (PLC-?), phosphatidylinositol-3 kinase (PI3K), mammalian target of rapamycin, p38 MAPK, c-Jun N-terminal kinase, Akt, Ras, Raf, ERK, MAPK) also blocked the effects of aripiprazole. Using proteomic analysis, we found that aripiprazole significantly increased levels of the heat shock protein Hsp90? in cultured cells. The effects of aripiprazole on NGF-induced neurite outgrowth were significantly attenuated by treatment with Hsp90? RNA interference, but not by the negative control of Hsp90?. These findings suggest that both 5-HT(1A) receptor activation and Ca(2+) signaling via IP(3) receptors, as well as their downstream cellular signaling pathways play a role in the promotion of aripiprazole-induced neurite outgrowth. Furthermore, aripiprazole-induced increases in Hsp90? protein expression may form part of the therapeutic mechanism for this drug. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypal |
| 60 | Curr. Pharm. Des. 2012 -1 18: 875-83 |
| PMID | 22288409 |
| Title | Sigma-1 receptor agonists as therapeutic drugs for cognitive impairment in neuropsychiatric diseases. |
| Abstract | Cognitive impairment is a core feature of patients with neuropsychiatric diseases such as schizophrenia and psychotic depression. The drugs currently used to treat cognitive impairment have significant limitations, ensuring that the search for more effective therapies remains active. Endoplasmic reticulum protein sigma-1 receptors are unique binding sites in the brain that exert a potent effect on multiple neurotransmitter systems. Accumulating evidence suggests that sigma-1 receptors play a role in both the pathophysiology of neuropsychiatric diseases, and the mechanistic action of some therapeutic drugs, such as the selective serotonin reuptake inhibitors (SSRIs), donepezil and neurosteroids. Among SSRIs, fluvoxamine, a potent sigma-1 receptor agonist, has the highest affinity at sigma-1 receptors. Sigma-1 receptor agonists greatly potentiate nerve-growth factor (NGF)-induced neurite outgrowth in PC12 cells, an effect that is antagonized by treatment with the selective sigma-1 receptor antagonist NE-100. Furthermore, phencyclidine (PCP)-induced cognitive impairment, associated with animal models of schizophrenia is significantly improved by sub-chronic administration of sigma-1 receptor agonists such as fluvoxamine, SA4503 (cutamesine) and donepezil. This effect is antagonized by co-administration of NE-100. A positron emission tomography (PET) study using the specific sigma-1 receptor ligand [11C]SA4503 demonstrates that fluvoxamine and donepezil bind to sigma-1 receptors in the healthy human brain. In clinical studies, some sigma-1 receptor agonists, including fluvoxamine, donepezil and neurosteroids, improve cognitive impairment and clinical symptoms in neuropsychiatric diseases. In this article, we review the recent findings on sigma-1 receptor agonists as potential therapeutic drugs for the treatment of cognitive impairment in schizophrenia and psychotic depression. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypal |
| 61 | Mol. Cells 2013 Dec 36: 534-41 |
| PMID | 24292945 |
| Title | Administration of mesenchymal stem cells and ziprasidone enhanced amelioration of ischemic brain damage in rats. |
| Abstract | Ziprasidone is a benzisothiazolyl piperazine derivative that was developed from the chemically related antipsychotic drug tiospirone, and it improves neurological functions of the ischemic brain and is effective in treatment of schizophrenia. Mesenchymal stem cells (MSCs) are considered as a leading candidate for neurological regenerative therapy because of their neural differentiation properties in damaged brain. We investigated whether the transplantation of neural progenitor cells (NPCs) derived from adipose mesenchymal stem cells combined with ziprasidone enhances neuroprotective effects in an animal model of focal cerebral ischemia. In combination therapy groups, significant reduction of infarct volume and improvement of neurological functions were observed at 3 days after middle cerebral artery occlusion (MCAO) compared with monotherapy. Co-administration of ziprasidone and NPCs enhanced the anti-apoptotic effect and reduced the number of terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL)-positive apoptotic cells compared with the NPCs alone group at 7 days after MCAO. Ziprasidone or the combination of ziprasidone and NPCs induced the expression of endogenous neurotrophic factor gene brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), and glial cell-derived neurotrophic factor (GDNF). The immunohistochemical investigation revealed that the ziprasidone and NPCs attenuated the increased intensity of microglial marker (Iba-1) in the infarcted cortical area. Moreover, the number of transplanted NPCs on day 7 with combination therapy was significantly higher than with NPCs alone. These effects might be responsible for improved functional behavior and increased survival of NPCs. Our finding indicates that combination therapy of ziprasidone and NPCs enhances neuroprotection against ischemic brain injury. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypal |
| 62 | Cell. Signal. 2013 Oct 25: 2060-8 |
| PMID | 23770287 |
| Title | Rit subfamily small GTPases: regulators in neuronal differentiation and survival. |
| Abstract | Ras family small GTPases serve as binary molecular switches to regulate a broad array of cellular signaling cascades, playing essential roles in a vast range of normal physiological processes, with dysregulation of numerous Ras-superfamily G-protein-dependent regulatory cascades underlying the development of human disease. However, the physiological function for many "orphan" Ras-related GTPases remain poorly characterized, including members of the Rit subfamily GTPases. Rit is the founding member of a novel branch of the Ras subfamily, sharing close homology with the neuronally expressed Rin and Drosophila Ric GTPases. Here, we highlight recent studies using transgenic and knockout animal models which have begun to elucidate the physiological roles for the Rit subfamily, including emerging roles in the regulation of neuronal morphology and cellular survival signaling, and discuss new genetic data implicating Rit and Rin signaling in disorders such as cancer, Parkinson's disease, autism, and schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypal |
| 63 | Cell. Signal. 2013 Dec 25: 2871-7 |
| PMID | 24055909 |
| Title | Mechanism of dopamine D2 receptor-induced Ca(2+) release in PC-12 cells. |
| Abstract | Intracellular Ca(2+) levels are tightly regulated in the neuronal system. The loss of Ca(2+) homeostasis is associated with many neurological diseases and neuropsychiatric disorders such as Parkinson's, Alzheimer's, and schizophrenia. We investigated the mechanisms involved in intracellular Ca(2+) signaling in PC-12 cells. The stimulation of NGF-differentiated PC-12 cells with 3?M ATP caused an early Ca(2+) release followed by a delayed Ca(2+) release. The delayed Ca(2+) release was dependent on prior ATP priming and on dopamine secretion by PC-12 cells. Delayed Ca(2+) release was abolished in the presence of spiperone, suggesting that it is due to the activation of D2 dopamine receptors (D2R) by dopamine secreted by PC-12 cells. This was shown to be independent of PKA activation but dependent on PLC activity. An endocytosis step was required for inducing the delayed Ca(2+) release. Given the importance of calcyon in clathrin-mediated endocytosis, we verified the role of this protein in the delayed Ca(2+) release phenomenon. siRNA targeting of calcyon blocked the delayed Ca(2+) release, decreased ATP-evoked IP3R-mediated Ca(2+) release, and impaired subsequent Ca(2+) oscillations. Our results suggested that calcyon is involved in an unknown mechanism that causes a delayed IP3R-mediated Ca(2+) release in PC-12 cells. In schizophrenia, Ca(2+) dysregulation may depend on the upregulation of calcyon, which maintains elevated Ca(2+) levels as well as dopamine signaling. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypal |
| 64 | J Clin Psychiatry 2014 Aug 75: e794-801 |
| PMID | 25191916 |
| Title | Combining serum protein concentrations to diagnose schizophrenia: a preliminary exploration. |
| Abstract | It is difficult for clinicians to diagnose schizophrenia solely based on interviews. We explored the diagnostic efficiency and predictive capability of serum biomarkers for schizophrenia. Levels of ? nerve growth factor (?-NGF), brain-derived neurotrophic factor (BDNF), interleukin 6 (IL-6), tumor necrosis factor ? (TNF-?), interferon ? (IFN-?), calcium binding protein S100?, myelin basic protein (MBP), and glial fibrillary acidic protein (GFAP) were measured in the sera of 278 schizophrenia patients, 240 depression and bipolar disorder patients, and 260 healthy controls. DSM-IV-TR criteria were used as the diagnostic criteria for schizophrenia and depressive and bipolar disorders. The diagnostic efficiency was high in patients with schizophrenia compared with the healthy controls. Receiver operating characteristic (ROC) curve analysis was used to ascertain the diagnostic efficiency of the 8 proteins. Data were collected between July 2010 and December 2012. One-way analysis of variance significantly demonstrated lower serum BDNF, MBP, and GFAP levels (F = 16.504, P < .001; F = 207.209, P < .001; F = 33.668, P < .001, respectively) but higher serum IL-6 and S100? concentrations (F = 15.250, P < .001; F = 12.751, P < .001, respectively) among patients with schizophrenia. ROC analysis of the discriminant scores of the serum ?-NGF, BDNF, IL-6, S100?, MBP, and GFAP levels resulted in significant discrimination between the schizophrenia and control groups (AUC = 0.922) and the depressive/bipolar disorder and control groups (AUC = 0.762). Serum levels of 6 proteins (but not TNF-? and IFN-?) contribute most to the diagnosis of schizophrenia. These proteins may prove to be useful adjuncts for the clinical assessment of this disease. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypal |
| 65 | Scand. J. Immunol. 2014 Jul 80: 36-42 |
| PMID | 24498860 |
| Title | Changes in serum levels of brain derived neurotrophic factor and nerve growth factor-beta in schizophrenic patients before and after treatment. |
| Abstract | schizophrenia is one of the most debilitating diseases among psychiatric disorders. Recent studies suggest the existence of effective immunological changes in the pathophysiology of this disease. The purpose of the current study was to determine the changes in serum levels of Brain Derived Neurotrophic Factor (BDNF) and Nerve Growth Factor-beta (NGF) in schizophrenic patients before treatment and 40 days after treatment. In this case-control study, serum levels of BDNF and NGF were measured by ELISA in 26 patients with schizophrenia and 26 healthy controls. All patients were treated with clozapine or risperidone for 40 days. A positive and negative syndrome scale (PANSS) questionnaire has been used to recognize the severity of the disease and to assess the response to treatment. Neurotrophin concentrations were compared before and after the treatment and with control groups using paired t-test and ANOVA test. BDNF and NGF levels in the case group were more than levels after treatment, but these differences were significant only for NGF. Concentrations in both neurotrophins were higher than the control group. The statistically significant difference was observed between changes in the NGF levels in the case and the control group, while no significant difference was seen in changes of BDNF. The main conclusion to be drawn from this study was that the increase in BDNF and particularly NGF may have an important role in causing schizophrenia. And possibly drugs clozapine and risperidone help to treat the disease by reducing the concentration of Neurotrophins. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypal |
| 66 | Scand. J. Immunol. 2014 Jul 80: 36-42 |
| PMID | 24498860 |
| Title | Changes in serum levels of brain derived neurotrophic factor and nerve growth factor-beta in schizophrenic patients before and after treatment. |
| Abstract | schizophrenia is one of the most debilitating diseases among psychiatric disorders. Recent studies suggest the existence of effective immunological changes in the pathophysiology of this disease. The purpose of the current study was to determine the changes in serum levels of Brain Derived Neurotrophic Factor (BDNF) and Nerve Growth Factor-beta (NGF) in schizophrenic patients before treatment and 40 days after treatment. In this case-control study, serum levels of BDNF and NGF were measured by ELISA in 26 patients with schizophrenia and 26 healthy controls. All patients were treated with clozapine or risperidone for 40 days. A positive and negative syndrome scale (PANSS) questionnaire has been used to recognize the severity of the disease and to assess the response to treatment. Neurotrophin concentrations were compared before and after the treatment and with control groups using paired t-test and ANOVA test. BDNF and NGF levels in the case group were more than levels after treatment, but these differences were significant only for NGF. Concentrations in both neurotrophins were higher than the control group. The statistically significant difference was observed between changes in the NGF levels in the case and the control group, while no significant difference was seen in changes of BDNF. The main conclusion to be drawn from this study was that the increase in BDNF and particularly NGF may have an important role in causing schizophrenia. And possibly drugs clozapine and risperidone help to treat the disease by reducing the concentration of Neurotrophins. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypal |
| 67 | Front Cell Neurosci 2014 -1 8: 80 |
| PMID | 24688456 |
| Title | Applying mass spectrometry-based qualitative proteomics to human amygdaloid complex. |
| Abstract | The amygdaloid complex is a key brain structure involved in the expression of behaviors and emotions such as learning, fear, and anxiety. Brain diseases including depression, epilepsy, autism, schizophrenia, and Alzheimer's disease, have been associated with amygdala dysfunction. For several decades, neuroanatomical, neurophysiological, volumetric, and cognitive approaches have been the gold standard techniques employed to characterize the amygdala functionality. However, little attention has been focused specifically on the molecular composition of the human amygdala from the perspective of proteomics. We have performed a global proteome analysis employing protein and peptide fractionation methods followed by nano-liquid chromatography tandem mass spectrometry (nanoLC-MS/MS), detecting expression of at least 1820 protein species in human amygdala, corresponding to 1814 proteins which represent a nine-fold increase in proteome coverage with respect to previous proteomic profiling of the rat amygdala. Gene ontology analysis were used to determine biological process represented in human amygdala highlighting molecule transport, nucleotide binding, and oxidoreductase and GTPase activities. Bioinformatic analyses have revealed that nearly 4% of identified proteins have been previously associated to neurodegenerative syndromes, and 26% of amygdaloid proteins were also found to be present in cerebrospinal fluid (CSF). In particular, a subset of amygdaloid proteins was mainly involved in axon guidance, synaptic vesicle release, L1CAM interactome, and signaling pathways transduced by NGF and NCAM1. Taken together, our data contributes to the repertoire of the human brain proteome, serving as a reference library to provide basic information for understanding the neurobiology of the human amygdala. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypal |
| 68 | BBA Clin 2014 Jun 1: 24-9 |
| PMID | 26675984 |
| Title | Nerve growth factor and its receptor in schizophrenia. |
| Abstract | Promising studies suggest that defects in synaptic plasticity detected in schizophrenia may be linked to neurodevelopmental and neurodegenerative abnormalities and contribute to disease-associated cognitive impairment. We aimed to clarify the role of the synaptic plasticity regulatory proteins, nerve growth factor (NGF) and its receptor (NGFR) in the pathogenesis of schizophrenia by comparative analysis of their blood levels and functional single nucleotide polymorphisms (SNPs) in genes encoding these proteins (NGF and NGFR) in schizophrenia-affected and healthy subjects. Relationships between the selected SNPs' genotypes and NGF and NGFR plasma levels were also assessed. Our results demonstrated a positive association between schizophrenia and the NGF rs6330 as well as the NGFR rs11466155 and rs2072446 SNPs. Also, a negative association between this disorder and NGF rs4839435 as well as NGFR rs734194 was found. In both, haloperidol-treated and antipsychotic-free patients decreased blood levels of the NGF and NGFR were found, and a positive interrelation between rs6330 and rs2072446 carriage and decreased NGF and NGFR levels, respectively, was revealed. In conclusion, our results demonstrate association of schizophrenia with the rs6330, rs4839435 and rs734194, rs11466155, rs2072446 as well as with the decreased blood levels of corresponding proteins. Our findings indicate the implication of alterations in NGFR and NGFR genes in schizophrenia, particularly, in defects of synaptic plasticity. Furthermore, the data obtained suggests that at least in Armenian population the NGF rs6330*T and NGFR rs11466155*T, rs2072446*T alleles might be nominated as risk factors, whereas the NGF rs4839435*A and NGFR rs734194*G alleles might be protective against developing schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypal |
| 69 | Genetika 2015 Jul 51: 799-811 |
| PMID | 26410934 |
| Title | [The Role of Neurotrophins and Neurexins Genes in the Risk of Paranoid Schizophrenia in Russians and Tatars]. |
| Abstract | schizophrenia affects about 1% of the population. Its etiology is not fully understood. Environmental conditions certainly contribute to the development of schizophrenia, but the determining factor is genetic predisposition: the coefficient of heritability of schizophrenia is about 80%, which is typical for the most highly heritable multifactorial diseases. Polymorphic loci of genes of enzymes and receptors involved in the processes of neuroprotection and neurotrophia play significant role in the development of this disease. In this paper we investigated 48 polymorphic variants of genes of the neurotrophins and neurexins family (BDNF, NTRK2, NTRK3, NGF, NXPH1, and NRXN1) in Russian and Tatar cases and in a control group living in the Republic of Bashkortostan. The results of this study confirm the important role of neurotrophin and neurexin genes in paranoid schizophrenia development. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypal |
| 70 | Life Sci. 2015 May 128: 79-93 |
| PMID | 25744402 |
| Title | Angiogenesis in the pathophysiology of schizophrenia - a comprehensive review and a conceptual hypothesis. |
| Abstract | -1 |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypal |
| 71 | Mol. Psychiatry 2015 Dec -1: -1 |
| PMID | 26666204 |
| Title | Polygenic associations of neurodevelopmental genes in suicide attempt. |
| Abstract | The risk for suicidal behavior (SB) is elevated in schizophrenia (SCZ), bipolar disorder (BPD) and major depressive disorder (MDD), but also occurs in subjects without psychiatric diagnoses. Genome-wide association studies (GWAS) on SB may help to understand this risk, but have been hampered by low power due to limited sample sizes, weakly ascertained SB or a reliance on single-nucleotide protein (SNP)-by-SNP analyses. Here, we tried to mitigate such issues with polygenic risk score (PRS) association tests combined with hypothesis-driven strategies using a family-based sample of 660 trios with a well-ascertained suicide attempt (SA) outcome in the offspring (Genetic Investigation of Suicide and SA, GISS). Two complementary sources of PRS information were used. First, a PRS that was discovered and validated in the GISS SA revealed the polygenic association of SNPs in 750 neurodevelopmental genes, which was driven by the SA phenotype, rather than the major psychiatric diagnoses. Second, a PRS based on three different genome-wide association studies (on SCZ, BPD or MDD) from the Psychiatric Genomics Consortium (PGC) showed an association of the PGC-SCZ PRS in the SA subjects with and without major psychiatric diagnoses. We characterized the PGC-SCZ overlap in the SA subjects without diagnoses. The extended major histocompatibility complex region did not contribute to the overlap, but we delineated the genic overlap to neurodevelopmental genes that partially overlapped with those identified by the GISS PRS. Among the 590 SA polygenes implicated here, there were several developmentally important functions (cell adhesion/migration, small GTPase and receptor tyrosine kinase signaling), and 16 of the SA polygenes have previously been studied in SB (BDNF, CDH10, CDH12, CDH13, CDH9, CREB1, DLK1, DLK2, EFEMP1, FOXN3, IL2, LSAMP, NCAM1, nerve growth factor (NGF), NTRK2 and TBC1D1). These novel genome-wide insights, supported by two lines of evidence, suggested the importance of a polygenic neurodevelopmental etiology in SB, even in the absence of major psychiatric diagnoses.Molecular Psychiatry advance online publication, 15 December 2015; doi:10.1038/mp.2015.187. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypal |
| 72 | Metab Brain Dis 2015 Aug 30: 1043-53 |
| PMID | 25920483 |
| Title | Maternal deprivation disrupts mitochondrial energy homeostasis in the brain of rats subjected to ketamine-induced schizophrenia. |
| Abstract | Maternal deprivation (MD) appears to be one of the environmental factors involved in the pathophysiology of schizophrenia. A widely used animal model of the schizophrenia involves the administration of ketamine, a dissociative anesthetic, NMDA receptors noncompetitive antagonist, that induce symptoms such as schizophrenia. To clarify the molecular mechanism of schizophrenia induced by MD, we investigated alterations in energetic metabolism, oxidative stress and neurotrophic factor levels in the brain of rats following MD and/or a single administration of ketamine during adulthood. Male Wistar rats were subjected to MD for 10 days. Additionally, these animals received acute ketamine (5, 15 or 25 mg/kg by intraperitoneal route, i.p.) during adulthood, and 30 min later, they were killed and the prefrontal cortex (PFC), the hippocampus and the striatum were removed for molecular analyses. Ketamine 25 mg/kg and/or MD and Ketamine 15 and 5 mg/kg with MD decreased the creatine kinase (CK) activity in the hippocampus. The enzyme activity of succinate dehydrogenase (SDH) in the Krebs cycle had increased in the striatum following the administration of ketamine 25 mg/kg, MD per se or MD plus ketamine 5 and 15 mg/kg. MD per se or MD combined with ketamine in different doses increased the activity of mitochondrial complexes. The PFC of animals subjected to MD and administered with ketamine 5 mg/kg exhibited increased protein carbonyl content. In the hippocampus, ketamine 15 mg/kg, ketamine 25 mg/kg and MD each increased the carbonyl content. In the striatum, the TBARS levels were increased by the administration of ketamine 25 mg/kg. Finally, in the hippocampus, MD alone or in combination with ketamine reduced the Nerve Growth Factor (NGF) levels; however, the Brain-derived Neurotrophic Factor (BDNF) levels were unaltered. In the present study, we suggest that MD increased the risk of psychotic symptoms in adulthood, altering different parameters of energy and oxidative stress. Our results suggest that adverse experiences occurring early in life may sensitize specific neurocircuits to subsequent stressors, inducing vulnerability, and may help us understand the pathophysiological mechanisms involved in this disorder. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypal |
| 73 | Eur Neuropsychopharmacol 2015 Apr 25: 505-11 |
| PMID | 25687838 |
| Title | Potentiation of neurite outgrowth by brexpiprazole, a novel serotonin-dopamine activity modulator: a role for serotonin 5-HT1A and 5-HT2A receptors. |
| Abstract | Brexpiprazole, a novel atypical antipsychotic drug, is currently being tested in clinical trials for treatment of psychiatric disorders, such as schizophrenia and major depressive disorder. The drug is known to act through a combination of partial agonistic activity at 5-hydroxytryptamine (5-HT)1A, and dopamine D2 receptors, and antagonistic activity at 5-HT2A receptors. Accumulating evidence suggests that antipsychotic drugs act by promoting neurite outgrowth. In this study, we examined whether brexpiprazole affected neurite outgrowth in cell culture. We found that brexpiprazole significantly potentiated nerve growth factor (NGF)-induced neurite outgrowth in PC12 cells, in a concentration dependent manner. The selective 5-HT1A receptor antagonist, WAY-100,635, was able to block the effects of brexpiprazole on neurite outgrowth, unlike the selective dopamine D2 receptor antagonist, raclopride. Furthermore, the selective 5-HT2A receptor antagonist M100907, but not DOI (5-HT2A receptor agonist), significantly potentiated NGF-induced neurite outgrowth. Moreover, xestospongin C and 2-aminoethoxydiphenyl borate (2-APB), both specific inhibitors of inositol 1,4,5-triphosphate (IP3) receptors, significantly blocked the effects of brexpiprazole. These findings suggest that brexpiprazole-induced neurite outgrowth is mediated through 5-HT1A and 5-HT2A receptors, and subsequent Ca(2+) signaling via IP3 receptors. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypal |
| 74 | Schizophr Bull 2016 Jan 42: 142-51 |
| PMID | 26130821 |
| Title | BDNF and NGF Signalling in Early Phases of Psychosis: Relationship With Inflammation and Response to Antipsychotics After 1 Year. |
| Abstract | Previous studies have indicated systemic deregulation of the proinflammatory or anti-inflammatory balance in individuals with first-episode psychosis (FEP) that persists 12 months later. To identify potential risk/protective factors and associations with symptom severity, we assessed possible changes in plasma levels of neurotrophins (brain-derived neurotrophic factor [BDNF] and nerve growth factor [NGF]) and their receptors in peripheral blood mononuclear cells (PBMCs). Expression of the 2 forms of BDNF receptors (active TrkB-FL and inactiveTrkB-T1) in PBMCs of FEP patients changed over time, TrkB-FL expression increasing by 1 year after diagnosis, while TrkB-T1 expression decreased. The TrkB-FL/TrkB-T1 ratio (hereafter FL/T1 ratio) increased during follow-up in the nonaffective psychosis group only, suggesting different underlying pathophysiological mechanisms in subgroups of FEP patients. Further, the expression of the main NGF receptor, TrkA, generally increased in patients at follow-up. After adjusting for potential confounders, baseline levels of inducible isoforms of nitric oxide synthase, cyclooxygenase, and nuclear transcription factor were significantly associated with the FL/T1 ratio, suggesting that more inflammation is associated with higher values of this ratio. Interestingly, the FL/T1 ratio might have a role as a predictor of functioning, a regression model of functioning at 1 year suggesting that the effect of the FL/T1 ratio at baseline on functioning at 1 year depended on whether patients were treated with antipsychotics. These findings may have translational relevance; specifically, it might be useful to assess the expression of TrkB receptor isoforms before initiating antipsychotic treatment in FEPs. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypal |
| 75 | Biol. Psychiatry 2016 Jun 79: 988-96 |
| PMID | 26212897 |
| Title | The Relationship of Common Risk Variants and Polygenic Risk for Schizophrenia to Sensorimotor Gating. |
| Abstract | Prepulse inhibition (PPI) of the startle reflex has been suggested as a candidate endophenotype for schizophrenia research, as it shows high heritability and has been found deficient in schizophrenia spectrum disorders. The objectives of the study were to 1) identify common genetic variants associated with baseline startle and PPI; 2) estimate the single nucleotide polymorphism heritability; and 3) examine the relationship of polygenic score for schizophrenia with baseline startle and PPI. A cohort of healthy young male subjects (n = 1493) originating from the Learning on Genetics of schizophrenia Spectrum project was assessed for baseline startle and PPI. The most recent genome-wide association study in schizophrenia from the Psychiatric Genomics Consortium 2 was used to calculate polygenic scores. Eleven loci showed suggestive association (p < 10(-6)) with baseline startle and PPI in the discovery cohort. Additional genotyping in a replication cohort identified genome-wide significant association at two loci (rs61810702 and rs4718984). These loci were co-localized with expression quantitative trait loci associated with gene expression of nerve growth factor (NGF) and calneuron 1 (CALN1) genes. Estimation of the genetic and environmental contributions to baseline startle and PPI showed a substantial single nucleotide polymorphism heritability for 120-ms PPI stimuli. Increased polygenic risk score for schizophrenia was associated with reduced PPI. Common genetic variation has an important role in the etiology of schizophrenia and PPI impairments. Overall, these data support the idea that PPI is a valid endophenotype that can be used to explore the genetic architecture of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypal |